Language：Japanese  

Web of Science

Language：Japanese   Publisher：European Journal of Cancer  

Background: Peripheral sensory neuropathy (PSN) caused by oxaliplatin-based adjuvant chemotherapy adversely affects patients' quality of life. This study evaluated the efficacy and safety of capecitabine plus oxaliplatin (CAPOX) with intermittent oxaliplatin use compared with the standard CAPOX in adjuvant therapy for colon cancer. Patients and methods: Patients with curative resection for stage II/III colon cancer were randomly assigned to receive either CAPOX with continuous oxaliplatin (eight cycles of CAPOX) or CAPOX with intermittent oxaliplatin (two cycles of CAPOX, four cycles of capecitabine and two cycles of CAPOX). The primary end-point was the 1-year PSN rate, and the key secondary end-point was disease-free survival (DFS). Results: Two hundred patients were enrolled in the intent-to-treat population. After 4 patients withdrew, 196 patients were included in the safety analysis. The overall treatment completion rate was 65% for continuous vs. 89% for intermittent treatment (p < 0.001). The 1-year PSN rate was 60% (95% confidence interval [CI], 50%–70%) for continuous and 16% (95% CI, 10%–25%) for intermittent treatment (p < 0.001). After a median follow-up of 52 months, 40 events (20%) were observed. The 3-year DFS was 81% (95% CI, 71%–87%) for continuous and 84% (95% CI, 75%–90%) for intermittent treatment (hazard ratio [HR], 0.87; 95% CI, 0.47–1.63). Among patients with high-risk disease (T4 or N2-3), the 3-year DFS was 57% for continuous vs. 74% for intermittent treatment (HR, 0.66). Conclusion: CAPOX with planned intermittent oxaliplatin may be feasible as an adjuvant therapy for colon cancer and substantially reduce the duration of long-lasting PSN. Trial identifier: UMIN000012535.

DOI： 10.1016/j.ejca.2020.11.007

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Molecular Therapy - Nucleic Acids  

Patients with peritoneal metastasis of gastric cancer have dismal prognosis, mainly because of inefficient systemic delivery of drugs to peritoneal tumors. We aimed to develop an intraperitoneal treatment strategy using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII (SYT13) and to identify the function of SYT13 in gastric cancer cells. We screened 71 candidate oligonucleotide sequences according to SYT13-knockdown efficacy, in vitro activity, and off-target effects. We evaluated the effects of SYT13 knockdown on cellular functions and signaling pathways, as well as the effects of intraperitoneal administration to mice of AmNA-modified anti-SYT13 ASOs. We selected the ASOs (designated hSYT13-4378 and hSYT13-4733) with the highest knockdown efficiencies and lowest off-target effects and determined their abilities to inhibit cellular functions associated with the metastatic potential of gastric cancer cells. We found that SYT13 interfered with focal adhesion kinase (FAK)-mediated intracellular signals. Intraperitoneal administration of hSYT13-4378 and hSYT13-4733 in a mouse xenograft model of metastasis inhibited the formation of peritoneal nodules and significantly increased survival. Reversible, dose- and sequence-dependent liver damage was induced by ASO treatment without causing abnormal morphological and histological changes in the brain. Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer.

DOI： 10.1016/j.omtn.2020.10.001

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Molecular Cancer  

Background: Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). Methods: Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr -/- mice, and assessed the clinical significance of NPTXR expression in GC specimens. Results: NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr -/- mice showed no abnormalities in reproduction, development, metabolism, or motor function. Conclusions: NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.

DOI： 10.1186/s12943-020-01251-0

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Translational Oncology  

BACKGROUND: Primary tumor location is a critical prognostic factor that also impacts the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in wild-type RAS (KRAS/NRAS) metastatic colorectal cancer (CRC). However, the association between the incidence of BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations and primary tumor location remains unclear. METHODS: We prospectively collected tumor samples and clinical data of patients from 15 hospitals between August 2014 and April 2016 to investigate RAS, BRAF, and PIK3CA mutations using a polymerase chain reaction-based assay. According to the primary tumor location, patients were classified to right-sided (from cecum to splenic flexure) and left-sided (from descending colon to rectum) tumor groups. RESULTS: In total, 577 patients with CRC were investigated, 331 patients (57%) had CRC with wild-type RAS; of these 331 patients, 10.5%, 4.8%, and 5.9% patients harbored BRAFV600E, BRAFnon-V600E, and PIK3CA mutations, respectively. BRAF/PIK3CA mutations were more frequent in females, patients with right-sided tumors, and patients with peritoneal metastasis cases and less frequent in patients with liver metastases. The prevalence rates of BRAFV600E and PIK3CA mutations were higher in patients with right-sided tumors than in those with left-sided tumors (32.3% vs. 4.8% and 17.2% vs. 3.6%, respectively). CONCLUSIONS: More than half of the patients with right-sided CRC and wild-type RAS harbored BRAF/PIK3CA mutations, including BRAFnon-V600E, which may contribute to the difference in the anti-EGFR efficacy between the right- and left-sided CRC.

DOI： 10.1016/j.tranon.2020.100786

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Annals of Surgical Oncology  

Background: We aimed to clarify the role of potassium voltage-gated channel subfamily J member 15 (KCNJ15) in esophageal squamous cell carcinoma (ESCC) cells and its potential as a prognosticator in ESCC patients. Methods: KCNJ15 transcription levels were evaluated in 13 ESCC cell lines and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with KCNJ15. The biological functions of KCNJ15 in cell invasion, proliferation, migration, and adhesion were validated through small interfering RNA-mediated knockdown experiments. Cell proliferation was further evaluated through the forced expression experiment. KCNJ15 expression was detected in 200 ESCC tissues by quantitative real-time reverse transcription PCR (qRT-PCR) and analyzed in 64 representative tissues by immunohistochemistry. Correlations between KCNJ15 expression levels and clinicopathological features were also analyzed. Results: The KCNJ15 expression levels varied widely in ESCC cell lines and correlated with COL3A1, JAG1, and F11R. Knockdown of KCNJ15 expression significantly repressed cell invasion, proliferation, and migration of ESCC cells in vitro. Furthermore, overexpression of KCNJ15 resulted in increased cell proliferation. Patients were stratified using the cut-off value of KCNJ15 messenger RNA (mRNA) levels in 200 ESCC tissues using receiver operating characteristic curve analysis; the high KCNJ15 expression group had significantly shorter overall and disease-free survival times. In multivariable analysis, high expression of KCNJ15 was identified as an independent poor prognostic factor. Staining intensity of in situ KCNJ15 protein expression tended to be associated with KCNJ15 mRNA expression levels. Conclusions: KCNJ15 is involved in aggressive tumor phenotypes of ESCC cells and its tissue expression levels may be useful as a prognosticator of patients with ESCC.

DOI： 10.1245/s10434-019-08189-8

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Annals of Surgical Oncology  

Background: Liver metastasis of gastric cancer (GC) is highly associated with poor prognosis. The development of sensitive biomarkers for detecting and predicting liver metastasis is required for better clinical outcome. Objective: In this study, we aimed to identify novel genes associated with liver metastasis of GC. Methods: Global expression profiling of 57,749 genes was performed using surgically resected gastric tissues from four patients with liver metastasis to identify candidate genes. The mRNA expression levels of the selected candidate gene were analyzed in the resected gastric tissues of 300 GC patients and correlated with clinicopathological parameters. Fourteen GC cell lines were subjected to mRNA expression and polymerase chain reaction (PCR) array analysis. Results: Among 25 candidate genes identified by transcriptome analysis, preferentially expressed antigen of melanoma (PRAME) was selected for subsequent analyses. mRNA expression analysis of clinical samples revealed the aberrant expression of PRAME in GC tissues, and its high expression was significantly related to differentiated phenotype and vessel invasion, as well as liver metastasis. High PRAME expression was significantly associated with hepatic recurrence after curative surgery, and cumulative incidences of hepatic recurrence were significantly greater in patients with high PRAME expression compared with patients with low PRAME expression. In an in vitro analysis, overexpression was observed in all GC cell lines compared with a normal epithelial cell line. PCR array analysis revealed the coordinate expression of MMP9, OCLN, IL1RN, and MST1R. Conclusions: PRAME is related to the malignant potential of GC and could serve as a novel biomarker for the detection and prediction of liver metastasis.

DOI： 10.1245/s10434-019-07985-6

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：International Journal of Cancer  

Liver metastasis is often fatal in patients with gastric cancer, therefore, we aimed to identify genes associated with the mechanisms of liver metastasis of gastric cancer (GC) and to investigate their potential to predict recurrence and to serve as targets of therapy. Recurrence pattern-specific transcriptome analysis was performed to identify liver metastasis-associated genes. A stable knockout cell line was generated to investigate metabolic pathways that contribute to the malignant phenotype in vitro and vivo. Three hundred GC patients were analyzed to demonstrate an association between gene expression levels and clinicopathological parameters. As a results extracellular matrix complex subunit 1 (FRAS1) was identified as a liver metastasis-associated gene. Pathway analysis revealed that FRAS1 expression was significantly correlated with the expression of genes encoding TGFB1, MAP1B, AHNAK, BMP2, MUC1, BIRC5, MET, CDH1, RB1 and MKI67. FRAS1 expression was associated with the activation of the EGFR and PI3K signaling pathways. The proliferation ability of FRAS1 knockout cell line (FRAS1-KO) was inhibited compared to that of the parent cell line through caspase activity increment and cell cycle alteration. FRAS1-KO cells exhibited increased responsiveness to oxygen stress and diminished stemness, invasiveness, and migration. Mouse models of GC revealed decreases in tumor formation and generation of metastasis by FRAS1-KO cells. Moreover, the cumulative liver recurrence rate was significantly increased in patients with GC with high FRAS1 expression levels. We concluded that FRAS1 contributes to the malignant phenotype of GC, especially liver metastasis, and may therefore serve as a predictive marker or a target for treating liver metastasis.

DOI： 10.1002/ijc.32705

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Gastric Cancer  

Background: Although peritoneal lavage cytology often serves as a sensitive method to detect free cancer cells in the abdominal cavity, some patients experience peritoneal recurrence despite negative cytology. The aim of this study was to evaluate mRNAs in peritoneal lavage fluid as potential markers for predicting the peritoneal recurrence of gastric cancer (GC). Methods: Peritoneal lavage fluid samples were obtained during surgery conducted on 187 patients with GC and from 30 patients with non-malignant disease (controls). The mRNA levels of nine candidate markers were quantified, and analysis of a receiver-operating characteristic curve compared their accuracies. The cutoff was defined as the highest value of the controls. Results: Synaptotagmin XIII (SYT13) and carcinoembryonic antigen (CEA) mRNA levels were analyzed further. SYT13 levels were significantly associated with shorter peritoneal recurrence-free survival (PRFS) and overall survival. Among patients with negative peritoneal lavage cytology, those positive for either SYT13 or CEA mRNA experienced significantly shorter peritoneal recurrence-free survival compared with those with negative fluid (hazards ratio [HR] 4.21, P = 0.0114; HR 3.53; P = 0.0426, respectively). Univariate analysis revealed that SYT13 and CEA mRNA levels were significant predictors of peritoneal recurrence. Positive levels of both SYT13 and CEA mRNA demonstrated the highest HR for peritoneal recurrence (HR 12.27, P = 0.0064). Multivariable analysis revealed that SYT13 positivity was a significant independent prognostic factor (HR 3.69; 95% confidence interval, 1.18–12.74; P = 0.0246). Conclusions: Combined measurement of SYT13 and CEA mRNA levels in peritoneal lavage fluid could serve as a promising approach to predict peritoneal recurrence of GC.

DOI： 10.1007/s10120-019-00967-3

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Anticancer Research  

Background/Aim: We previously reported that expression of melanoma-associated antigen (MAGE)-D4 mRNA was a prognostic factor for esophageal squamous cell carcinoma (ESCC). The aim of this study was to validate the expression of MAGE-D4 in two additional patient cohorts, and to investigate its biological functions. Materials and Methods: The role of MAGE-D4 in cell proliferation, adhesion, and migration was determined by gene knockdown experiments in the KYSE590 cell line. MAGE-D4 protein expression was analyzed in ESCC tissues by immunohistochemistry. A second validation cohort consisted of an ESCC mRNA dataset from The Cancer Genome Atlas. Results: Knockdown of MAGE-D4 significantly decreased cell proliferation and migration. Expression of MAGE-D4 protein was significantly associated with disease-free survival. In the second validation cohort, high MAGE-D4 mRNA expression was associated with significantly shorter overall survival and disease-free survival. Conclusion: MAGE-D4 plays an important role in the malignant behavior of ESCC. MAGE-D4 was validated as a prognostic indicator in two independent ESCC patient cohorts.

DOI： 10.21873/anticanres.13807

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Anticancer Research  

Background/Aim: To investigate the function of preferentially expressed antigen of melanoma (PRAME) in esophageal squamous cell carcinoma (ESCC). Materials and Methods: mRNA expression levels of PRAME were analyzed in resected esophageal tissues of 150 ESCC patients and correlated with clinicopathological parameters. We also investigated the potential function of PRAME by analyzing coordinately expressed genes in 13 ESCC cell lines. Results: RT-qPCR analysis of clinical samples revealed aberrantly high PRAME expression in tumors compared with normal esophageal tissues. High PRAME expression was significantly associated with shorter disease-specific survival and hematogenous recurrence, but not with overall recurrence. The cumulative incidence of hematogenous recurrence was significantly greater for patients with high compared to those with low PRAME expression. In vitro, PCR array analysis revealed that PRAME was coordinately expressed with EGFR, ITGB, and TCF3. Conclusion: PRAME is overexpressed in ESCC tissues and may serve as a novel biomarker for predicting hematogenous recurrence.

DOI： 10.21873/anticanres.13799

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Anticancer Research  

Aim: The aim of the study was to identify novel biomarkers that are vital for improving management of patients with gastric cancer (GC). Materials and Methods: An RNA-sequencing analysis was conducted using gastric tissue from patients with metastatic GC. In vitro cell functions were evaluated by siRNA-mediated knockdown assays. A total of 230 pairs of gastric tissue were subjected to expression analysis of mRNA and protein in situ. The serum levels of the candidate biomarker were determined by ELISA. Results: MELTF was identified as a candidate biomarker. Inhibition of MELTF expression suppressed the invasion ability of GC cells. Increased tissue MELTF mRNA expression was associated with shorter survival. Furthermore, staining intensity of tissue MELTF protein was linked to recurrence rates. Serum MELTF levels gradually were increased from healthy controls to advanced GC. Patients with high serum MELTF levels had poor prognosis. Conclusion: Both tissue and serum MELTF levels may serve as biomarkers of GC progression.

DOI： 10.21873/anticanres.13820

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Expert Review of Molecular Diagnostics  

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide and recurrence rate after curative resection remains high. To improve HCC prognosis, novel sensitive biomarkers and targeted molecular therapies are needed. Accumulation of multiple genetic aberrations caused by pathologically derived liver damage results in HCC carcinogenesis. Elucidating the genes associated with tumorigenesis and progression of HCC may lead to the development of early detection and prognosis markers and to the identification of therapeutic targets. Areas covered: We review recently reported (January 2017-March 2019) HCC-associated molecules, including protein-coding genes, microRNAs, long non-coding RNAs, and methylated gene promoters. Expert opinion: The molecules reviewed have the potential to be clinical biomarkers and therapeutic targets for HCC. The accumulation and understanding of genetic and epigenetic data are essential to improve the management of HCC patients.

DOI： 10.1080/14737159.2019.1638254

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Brain Structure and Function  

With the objective to investigate the role of the insula in recognizing emotion, we performed direct electrical stimulation over the anterior insular cortex during awake surgery while simultaneously delivering an emotional sensitivity task. We registered 18 consecutive patients with brain tumors associated with the insular lobe, who were undergoing tumor resection. An emotional sensitivity task was employed to measure the patients’ ability to recognize emotions from facial expressions before, during, and after awake surgery. Furthermore, we performed voxel-based lesion symptom mapping (VLSM) to identify the association between relevant brain lesions and emotion recognition. When we performed direct electrical stimulation over the anterior insular cortex during awake surgery, the results showed that the ability to recognize anger was significantly enhanced with the presence of anterior insular stimulation (p < 0.05). Comparing the performance in the emotional sensitivity task before and after surgery, the performance in the anger condition became worse (p < 0.01), but became better in the sadness condition after surgery (p < 0.01). In the case of anger recognition, lower scores in the correct response index were associated with lesions involving the left insula in the VLSM study. Direct electrical stimulation over the anterior insular cortex enhanced anger recognition in patients with insular tumors. In contrast, accuracy of anger recognition was significantly reduced, and sadness was improved, when the performance of emotional sensitivity was compared pre- and post-surgery. Our findings suggest that the insular cortex is involved in changes in emotion recognition, including anger and sadness recognition by modulating arousal level that is closely connected with interoception.

DOI： 10.1007/s00429-019-01895-9

Web of Science

Scopus

Language：Japanese   Publisher：Annals of Surgical Oncology  

Background: The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa. Methods: Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer. Results: PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis. Conclusions: Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy.

DOI： 10.1245/s10434-019-07166-5

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Frontiers in Psychology  

Episodic future simulation is supported by both the retrieval and recombination of episodic details. It remains unclear, however, how individuals retrieve episodic details from memory to construct possible future scenarios; for this people must use details related to the planned future events appropriately. A potentially relevant cognitive process is the spontaneous activation of intention observed in prospective memory (i.e., the intention superiority effect). Previous studies on prospective memory have shown that the approximation of retrieval opportunities for future intentions activate related information, suggesting that the intention superiority effect is context-sensitive. We hypothesized that the same cognitive process underlies future simulation-that is, details related to future events should spontaneously become activated at the appropriate moment of future simulation to make that simulation plausible. In Experiment 1, participants took part in future experiments and formed intentions to perform particular actions for the next experiments. Subsequently, they imagined events that could occur up until they arrived at the experimental room on the day of the next experiment. During this exercise, they did not imagine engaging in the required experimental task. We measured the conceptual activation of intention-related information via a recognition task using intended action words as targets. The results showed the intention superiority effect-concepts related to participants' future intentions became active when envisioning future events approaching the next experiment. In Experiments 2 and 3, we ensured that the intention superiority effect in future simulation was context-sensitive by adding a control condition that required participants to imagine events other than the approaching future experiments. These results indicated that concepts related to the intended actions were spontaneously activated when imagined future events became both temporally and spatially close to the future simulation. Our finding suggests that spontaneous activation of details approaching the context of a future simulation helps in constructing plausible future scenarios.

DOI： 10.3389/fpsyg.2019.00625

Web of Science

Scopus

Language：Japanese   Publisher：Annals of Surgical Oncology  

Background: Identification of gastric cancer-related molecules is necessary to elucidate the pathological mechanisms of this heterogeneous disease. The purpose of this study was to identify novel genes associated with aggressive phenotypes of gastric cancer. Methods: Global expression profiling was conducted using tissues from four patients with metastatic gastric cancer to identify genes overexpressed in gastric cancer. Fifteen gastric cell lines and 262 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. The contribution of the candidate gene on gastric cancer cell proliferation, invasion, adhesion, and migration were evaluated using small interfering RNA. Results: DnaJ heat shock protein family (Hsp40) member C12 (DNAJC12) was identified as a candidate gene by transcriptome analysis. In clinical samples, DNAJC12 mRNA levels were higher in gastric cancer tissues compared with normal adjacent tissues. Patients with high DNAJC12 expression showed significantly shorter overall survival in our cohort and in the extra-validation cohort analyzed by a published microarray dataset. High DNAJC12 expression in gastric cancer tissues was significantly associated with lymphatic involvement, infiltrative growth type, lymph node metastasis, and advanced stage and was identified as an independent prognostic factor for overall survival in multivariable analysis. Increased expression of DNAJC12 was found in 12 of 14 examined gastric cancer cell lines. Knockdown of DNAJC12 expression significantly decreased the proliferation and invasion abilities of gastric cancer cells. Conclusions: Our findings support DNAJC12 as a candidate gene associated with aggressive phenotypes of gastric cancer.

DOI： 10.1245/s10434-018-07149-y

Web of Science

Scopus

PubMed

Language：Japanese  

Web of Science

Language：Japanese   Publisher：Annals of Cancer Research and Therapy  

The combination regimen of cisplatin (CDDP) and fluorouracil (5-FU) (FP) is a standard regimen for definitive chemora-diotherapy, neoadjuvant chemotherapy, and for treatment of unresectable or recurrent esophageal squamous cell carcinoma (ESCC). Here, we report a patient with FP-induced renal salt-wasting syndrome (RSWS) who presented with severe hyponatremia with disturbance of consciousness and was admitted to the intensive care unit (ICU). A 66-year-old man with recurrent ESCC was admitted and started on chemotherapy with FP. From day 3 of the first course of FP, he presented with anorexia and vomiting (grade 3). At day 6, he experienced disturbance of consciousness and blood test showed severe hyponatremia (sodium (Na): 119 mmol/L) accompanied with excessive urinary excretion of Na (181 mmol/L). He was diagnosed with RSWS because of CDDP and was transferred to the ICU. Through intensive monitoring and 3% NaCl infusion, serum Na level and symptoms recovered with no sequelae and he was discharged from the ICU after a 4-day stay. RSWS is sometimes difficult to diagnose because of its low recognition and is misdiagnosed as the syndrome of inappropriate secretion of antidiuretic hormone. During chemotherapy with platinum-based agents, RSWS should be kept in mind as a disorder that causes hyponatremia.

DOI： 10.4993/acrt.27.64

Scopus

Language：Japanese   Publisher：In Vivo  

Background/Aim: Establishment of mouse xenograft models is necessary for oncological research and depends on the characteristics of the cell lines and the immune system of the host. In this study, we describe the development of mouse xenograft models using human gastric cancer (GC) cell lines. Materials and Methods: MKN1 stably-expressing luciferase (MKN1-Luc), N87, KATO III, MKN45 stably-expressing luciferase (MKN45-Luc), NUGC4, and OCUM-1 human GC cell lines were injected intraperitoneally into mice to establish peritoneal metastasis models. MKN45-Luc were injected into subcutaneously implanted spleen, and MKN1-Luc and MKN45-Luc were injected directly into the portal veins of mice for the establishment of hepatic metastasis models. Results: Peritoneal metastasis was formed after implantation of MKN1-Luc, N87, KATO III, MKN45-Luc, and NUGC4 in nude mice, but not formed in OCUM-1 even in NOD/SCID mice. After intrasplenic injection of MKN45-Luc, we found no hepatic metastasis formation. We identified hepatic metastasis formation after direct injection of MKN45-Luc and MKN1-Luc into the portal veins of NOD/SCID mice. Conclusion: Peritoneal and hepatic metastasis mouse xenograft models were successfully established using several human GC cell lines.

DOI： 10.21873/invivo.11669

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Oncology Letters  

Breast cancer (BC) is the most frequently diagnosed malignant tumor in women worldwide, and the development of new molecules associated with BC is essential for the management of this disease. RAS and EF-hand domain-containing (RASEF) encodes the GTPase enzyme that belongs to the Rab family. Although the effects of this gene have been reported in several malignant tumor types, the role of RASEF in BC has not been completely elucidated. The aim of the present study was to investigate the importance of RASEF expression in BC. RASEF mRNA expression levels were evaluated in BC and non-cancerous mammary cell lines. The association between RASEF mRNA expression levels and clinicopathological factors in 167 patients with BC were then determined. Among the 13 examined BC cell lines, ER-negative/HER2-negative cell lines expressed lower RASEF mRNA levels, when compared with the other examined cell lines (P=0.014). Of the 167 patients examined, patients with negative hormone receptor status exhibited significantly lower RASEF mRNA expression levels (P<0.001). In addition low RASEF expression in BC tissues was associated with negative estrogen receptor status (P<0.001), negative progesterone receptor status (P<0.001), and triple-negative status (P<0.001). Additionally, although the differences were not statistically significant, patients with low RASEF expression levels exhibited poorer disease-free survival (P=0.123) and overall survival (P=0.086) than other patients. The results of the present study indicate that RASEF mRNA expression levels are associated with hormone receptor status in BC.

DOI： 10.3892/ol.2018.9542

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Oncology Reports  

Patients with esophageal squamous cell carcinoma (ESCC) have a poor prognosis. Identification of biomarkers to accurately predict the risk of recurrence and survival following curative esophageal resection is required to improve patient outcomes. The copine 5 (CPNE5) gene encodes a calcium-dependent lipid-binding intracellular protein. Copine proteins interact with diverse target proteins that are components of pathways that aberrantly regulate the phenotypes of malignant cells. However, limited information is available on the role of CPNE5 in cancer. The present study investigated whether CPNE5 may serve as a predictive marker of the prognosis of patients with ESCC following curative resection. CPNE5 mRNA expression levels and the methylation status of the CPNE5 promotor region were measured in 11 ESCC cell lines. CPNE5 mRNA expression levels in 106 pairs of surgically resected specimens were measured, and their associations with clinicopathological characteristics were analyzed. The CPNE5 mRNA expression levels in 9 ESCC cell lines were decreased compared with those of the non-tumorigenic esophageal mucosa cell line Het-1A. Bisulfite sequencing detected the methylation of the CPNE5 promotor region in all cell lines tested, including Het-1A. Furthermore, analysis of tissues revealed that CPNE5 m RNA expression was significantly lower in ESCC cells compared with cognate non-cancerous adjacent mucosal cells. Kaplan-Meier analysis revealed that patients with low CPNE5 expression experienced significantly shorter overall survival. Multivariable analysis identified low CPNE5 expression to be an independent prognostic factor of OS. Analysis of recurrence patterns revealed that significantly more patients with local recurrence expressed lower levels of CPNE5 mRNA. These findings indicated that CPNE5 expression in ESCC tissues may serve as an informative biomarker for predicting ESCC recurrence, particularly in patients with local recurrence, and may help to ensure that patients receive optimal treatment and follow.up.

DOI： 10.3892/or.2018.6742

Web of Science

Scopus

PubMed

Language：Japanese  

Web of Science

Language：Japanese   Publisher：Cancer Medicine  

Hepatic recurrence of gastric cancer (GC) is uncontrollable. Discovery of causative oncogenes and the development of sensitive biomarkers to predict hepatic recurrence are required to improve patients’ outcomes. In this study, recurrence pattern-specific transcriptome analysis of 57 749 genes was conducted to identify mRNAs specifically associated with hepatic metastasis of patients with stage III GC who underwent curative resection. GC cell lines were subjected to mRNA expression analysis, PCR array analysis, and siRNA-mediated knockdown. The expression levels of primary cancer tissues from 154 patients with resectable GC were determined and correlated with clinicopathological variables. Among 21 genes significantly overexpressed specifically in patients with hepatic recurrence, Sushi domain containing 2 (SUSD2) was selected as a promising target. PCR array analysis revealed that SUSD2 mRNA levels positively correlated with those of FZD7, CDH2, TGFB1, SPARC, ITGA5, and ZEB1. Functional analysis revealed that knockdown of SUSD2 significantly reduced the proliferation, migration, and invasiveness GC cell lines. Patients with high SUSD2 expression were more likely to experience shorter disease-free and overall survival. Analysis of the relation between disease recurrence pattern and SUSD2 levels revealed that significantly more patients with hepatic metastases expressed higher levels of SUSD2 mRNA. The cumulative incidence of hepatic recurrence was greater in patients with high SUSD2 expression. In conclusion, SUSD2 likely contributes to the malignant potential of GC and may serve as a novel biomarker that predicts hepatic recurrence after curative resection.

DOI： 10.1002/cam4.1793

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Oncogene  

Liver metastasis remains a serious problem in the management of gastric cancer (GC). Our aims were to identify through transcriptome analysis a molecule that mediates hepatic metastasis in GC, and to evaluate its potential as a diagnostic marker and a therapeutic target. The effects of knocking out a relevant molecule using genome editing were evaluated in vitro experiments and in mouse xenograft models. Expression levels of candidate molecule in 300 pairs of gastric tissues were determined to assess whether differentially expressed genes predicted hepatic recurrence, metastasis, or both. Transcriptome data identified the overexpression of synaptotagmin VII (SYT7) in GC tissues with hepatic metastasis. Its expression in the GC cell lines was high, particularly in those that exhibited a differentiated phenotype, and positively correlated with the expression of SNAI1 and TGFB3, and inversely with RGS2. SYT7 knockout inhibited the proliferation of GC cells, indicated by increased apoptosis with activated caspase and loss of mitochondria membrane potential, G2/M cell-cycle arrest and attenuated cell migration, invasion, and adhesion. The tumorigenicity of SYT7-knockout cells was moderately reduced in a mouse model of subcutaneous metastasis in which the levels of BCL2 and HIF1A were decreased and was more strikingly attenuated in a model of hepatic metastasis. The SYT7 levels in the primary GC tissues were significantly associated with hepatic recurrence, metastasis, and adverse prognosis. SYT7 represents a tool for prediction and monitoring of hepatic metastasis from GC as well as being a promising therapeutic target.

DOI： 10.1038/s41388-018-0335-8

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Molecular Cancer Research  

Hematogenous recurrence is a challenging clinical finding that often leads to fatalities of patients with gastric cancer. Therefore, the identification of specific biomarkers and potential therapeutic target molecules for hematogenous recurrence is required to improve the outcomes of these patients. Here, transcriptome and bioinformatics analyses were conducted to uncover candidate molecules differentially expressed in patients with hematogenous recurrence of gastric cancer. One potential candidate identified was asialoglycoprotein receptor 2 (ASGR2), and siRNA experiments were conducted to determine the effect of manipulating ASGR2 expression has on cell phenotypes. ASGR2 mRNA expression analysis using quantitative real-time reverse-transcription PCR was conducted with stage II/III gastric cancer clinical specimens (n ¼ 95). Transcript levels were increased in gastric cancer cells as compared with a control nontumorigenic epithelial cell line. Knockdown of ASGR2 decreased the adhesion and migration potential. Thus, although gastric cancer cell–invasive activity was significantly decreased by knockdown, forced expression of ASGR2 promoted invasive activity. Using a mouse hepatic metastasis model, knockdown of ASGR2 resulted in the absence of hepatic metastasis formation. High ASGR2 expression in primary gastric cancer tissues was an independent predictor of shorter disease-free and overall survival. Finally, patients with high ASGR2 expression were more likely to have a high cumulative rate of hematogenous recurrence but not peritoneal or nodal recurrence. Implications: ASGR2 expression is associated with the malignant phenotypes in gastric cancer and represents a specific biomarker of hematogenous recurrences after curative resection for gastric cancer.

DOI： 10.1158/1541-7786.MCR-17-0467

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Oncologist  

Purpose: The aim of this randomized, multicenter, noncomparative, phase II trial was to investigate the efficacy and safety of two potential first-line treatments, capecitabine and oxaliplatin (CapOX) plus bevacizumab (BEV) and capecitabine and irinotecan (CapIRI) plus bevacizumab, in Japanese patients with metastatic colorectal cancer (mCRC). Patients and Methods: Patients with untreated mCRC were randomly assigned to receive either CapOX plus bevacizumab (CapOX/BEV arm: bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 2,000 mg/m2 on days 1–14, every 3 weeks) or CapIRI plus bevacizumab (CapIRI/BEV arm: bevacizumab 7.5 mg/kg and irinotecan 200 mg/m2 on day 1 and capecitabine 1,600 mg/m2 on days 1–14, every 3 weeks). The primary endpoint was overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 107 patients were enrolled. The intent-to-treat population comprised 54 patients in the CapOX/BEV arm and 53 patients in the CapIRI/BEV arm. The median follow-up period was 35.5 months. ORR was 56% in the CapOX/BEV arm and 55% in the CapIRI/BEV arm. Median PFS and OS were 12.4 and 26.7 months in the CapOX/BEV arm and 11.5 and 28.7 months in the CapIRI/BEV arm, respectively. The frequencies of hematological and nonhematological adverse events above grade 3 were 13% and 30% in the CapOX/BEV arm and 25% and 23% in the CapIRI/BEV arm, respectively. Conclusion: CapOX plus bevacizumab and CapIRI plus bevacizumab are equally effective and feasible as the first-line treatments in Japanese patients with mCRC. Implications for Practice: The CCOG-1201 study was designed to evaluate the efficacy and safety of capecitabine and oxaliplatin plus bevacizumab and capecitabine and irinotecan plus bevacizumab as a first-line treatment in Japanese patients with metastatic colorectal cancer. This article reports on the trial and efforts to define the role of these regimens, including the effect of KRAS status and UGT1A1 polymorphisms in metastatic colorectal cancer.

DOI： 10.1634/theoncologist.2017-0640

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Annals of Surgical Oncology  

Background: Although peritoneal metastasis is a serious concern in patients with gastric cancer, no acceptable and specific biomarker is available. We aimed to identify a candidate biomarker to predict peritoneal metastasis of gastric cancer. Methods: Metastatic pathway-specific transcriptome analysis was conducted by comparison of patient groups with no recurrence and with peritoneal, hepatic, and nodal recurrence. Fifteen cell lines and 262 pairs of surgically resected gastric tissues were subjected to messenger RNA (mRNA) expression analysis. Polymerase chain reaction array analysis was performed to explore coordinately expressed cancer-related genes. To evaluate the in situ protein localization and expression patterns, immunohistochemical staining was performed. Results: From transcriptome data, troponin I2 (TNNI2) was identified as a candidate molecule specifically overexpressed in gastric cancer prone to peritoneal metastasis. TNNI2 mRNA was expressed at differential levels, independent of differentiated phenotype of cell lines. Epithelial to mesenchymal transition-related genes, tumor inhibitor of metalloproteinase 1 (TIMP1), and vacuolar protein sorting 13 homolog A (VPS13A) were expressed with TNNI2 at correlation coefficient > 0.7. The optimal cutoff of TNNI2 expression was determined as 0.00017. High TNNI2 expression was significantly and specifically associated with peritoneal metastasis and served as an independent risk marker for peritoneal recurrence after curative gastrectomy. Prevalence of peritoneal recurrence increased in parallel with staining intensity of TNNI2. Conclusions: TNNI2 expression in gastric tissues may serve as a specific biomarker for prediction of peritoneal metastasis of gastric cancer and contribute to improvement of patient management.

DOI： 10.1245/s10434-018-6480-z

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Cancer Medicine  

Development of specific biomarkers is necessary for individualized management of patients with gastric cancer. The aim of this study was to design a simple expression panel comprising novel molecular markers for precise risk stratification. Patients (n = 200) who underwent gastrectomy for gastric cancer were randomly assigned into learning and validation sets. Tissue mRNA expression levels of 15 candidate molecular markers were determined using quantitative PCR analysis. A dual-marker expression panel was created according to concordance index (C-index) values of overall survival for all 105 combinations of two markers in the learning set. The reproducibility and clinical significance of the dual-marker expression panel were evaluated in the validation set. The patient characteristics of the learning and validation sets were well balanced. The C-index values of combinations were significantly higher compared with those of single markers. The panel with the highest C-index (0.718) of the learning set comprised SYT8 and MAGED2, which clearly stratified patients into low-, intermediate-, and high-risk groups. The reproducibility of the panel was demonstrated in the validation set. High expression scores were significantly associated with larger tumor size, vascular invasion, lymph node metastasis, peritoneal metastasis, and advanced disease. The dual-marker expression panel provides a simple tool that clearly stratifies patients with gastric cancer into low-, intermediate-, and high risk after gastrectomy.

DOI： 10.1002/cam4.1522

Web of Science

Scopus

PubMed

Language：English   Publisher：Oncotarget  

Most of the proposed individual markers had limited clinical utility due to the inherent biological and genetic heterogeneity of gastric cancer. We aimed to build a new molecular-based model to predict prognosis in patients with gastric cancer. A total of 200 patients who underwent gastric resection for gastric cancer were divided into learning and validation cohorts using a table of random numbers in a 1:1 ratio. In the learning cohort, mRNA expression levels of 15 molecular markers in gastric tissues were analyzed and concordance index (C-index) values of all single and combinations of the 15 candidate markers for overall survival were calculated. The multigene expression panel was designed according to C-index values and the subpopulation index. Expression scores were determined with weighting according to the coefficient of each constituent. The reproducibility of the panel was evaluated in the validation cohort. C-index values of the 15 single candidate markers ranged from 0.506-0.653. Among 32,767 combinations, the optimal and balanced expression panel comprised four constituents (MAGED2, SYT8, BTG1, and FAM46) and the C-index value was 0.793. Using this panel, patients were provisionally categorized with scores of 1-3, and clearly stratified into favorable, intermediate, and poor overall survival groups. In the validation cohort, both overall and disease-free survival rates decreased incrementally with increasing expression scores. Multivariate analysis revealed that the expression score was an independent prognostic factor for overall survival after curative gastrectomy. We developed an integrated multigene expression panel that simply and accurately stratified risk of patients with gastric cancer.

DOI： 10.18632/oncotarget.24661

Scopus

PubMed

Language：Japanese   Publisher：Histology and Histopathology  

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Patients with HCC generally present at an advanced stage resulting in death within 6-20 months. Therefore, novel treatment modalities and sensitive prognostic markers that can decrease the mortality rate of HCC are required. HCC is a complex and heterogeneous tumor with multiple genetic aberrations. It has been well described that accumulation of genetic and epigenetic changes leads to the clonal selection of cancer cells harboring aggressive tumor behavior. Aberrant expression of cancer-related genes is one of the hallmarks of cancer cells and plays a role in hepatocarcinogenesis. Epigenetic alterations, such as the alteration of DNA methylation and histone modification in cancer cells, can also induce the activation and inactivation of cancer-related genes. Studies have shed light on the link between HCC-related genes and molecules, and a better understanding of the mechanisms of HCC pathogenesis could be translated into clinical biomarker tools. Moreover, analyses of genetic and epigenetic alterations have identified potential biomarkers that might be targeted therapeutically. In this review, we update the current knowledge of biomarkers in HCC, examine recently published literature, and introduce some representative molecules in each category.

DOI： 10.14670/HH-11-936

Web of Science

Scopus

PubMed

Language：Japanese  

Web of Science

Language：Japanese  

Web of Science

Language：Japanese  

DOI： 10.1016/j.ijscr.2018.08.047

Web of Science

PubMed

Language：Japanese  

Web of Science

Language：Japanese   Publisher：Annals of Surgical Oncology  

Background: Challenges to our understanding the molecular mechanisms of the progression of gastric cancer (GC) must be overcome to facilitate the identification of novel biomarkers and therapeutic targets. In this article, we analyzed the expression of the gene encoding F-box-only 50 (FBXO50) and determined whether it contributes to the malignant phenotype of GC. Methods: FBXO50 messenger RNA (mRNA) levels and copy numbers of the FBXO50 locus were determined in 10 GC cell lines and a nontumorigenic epithelial cell line. Polymerase chain reaction array analysis was performed to identify genes coordinately expressed with FBXO50. The effects of inhibiting FBXO50 on GC cell proliferation, adhesion, invasiveness, and migration were evaluated using a small interfering RNA targeted to FBXO50 mRNA. To evaluate the clinical significance of FBXO50 expression, we determined the levels of FBXO50 mRNA in tissues acquired from 200 patients with GC. Results: The levels of FBXO50 mRNA were increased in five GC cell lines and positively correlated with those of ITGA5, ITGB1, MMP2, MSN, COL5A2, GNG11, and WNT5A. Copy number gain of the FBXO50 locus was detected in four GC cell lines. Inhibition of FBXO50 expression significantly decreased the proliferation, adhesion, migration, and invasiveness of GC cell lines. In clinical samples, high FBXO50 expression correlated with increased pT4, invasive growth, lymph node metastasis, and positive peritoneal lavage cytology. Patients with high FBXO50 expression had a significantly higher prevalence of recurrence after curative gastrectomy and were more likely to experience shorter overall survival. Conclusions: FBXO50 may represent a biomarker for GC phenotypes and as a target for therapy.

DOI： 10.1245/s10434-017-5882-7

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Oncology Letters  

The poor prognosis and increasing incidence of esophageal squamous cell carcinoma (ESCC) highlight the need for identification of novel ESCC-associated molecular events to improve the diagnosis, and treatment of this disease. Non-specific cytotoxic cell receptor protein 1 (NCCRP1) was reported to be abundantly expressed in human squamous epithelium and to be involved in cell proliferation; however, the role of NCCRP1 in ESCC remains unclear. To elucidate the oncological roles of NCCRP1 in ESCC, NCCRP1 expression, DNA methylation, and copy numbers were analyzed in ESCC cell lines. Nine ESCC cell lines demonstrated different NCCRP1 mRNA expression levels and all exhibited hypermethylation of the NCCRP1 promoter, but no copy number loss. Additionally, NCCRP1 expression was determined in 213 surgically resected esophageal tissue samples. NCCRP1 mRNA expression levels were reduced in ESCC tissues compared with corresponding non-cancerous adjacent tissues in 204 (95.8%) patients. Patients in the low NCCRP1 expression group tended to have a higher recurrence rate and a shorter overall survival time compared with those in the high NCCRP1 expression group. Additionally, multivariate analysis revealed that low NCCRP1 expression was an independent prognostic factor (hazard ratio, 1.75; 95% confidence interval, 1.08‑2.87; P=0.022). The findings of the current study indicate that NCCRP1 acts as a putative tumor suppressor that is inactivated through promoter hypermethylation, and serves as a promising biomarker to predict postoperative prognosis in ESCC.

DOI： 10.3892/ol.2017.6753

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Oncotarget  

Hepatocellular carcinoma (HCC) frequently recurs even after curative hepatectomy. To develop an integrated multigene expression panel, 144 patients were randomly assigned to either discovery or validation set in a 1:2 ratio. Using surgically resected HCC specimens, expression levels of 12 candidate molecular markers were determined using quantitative reverse-transcriptase PCR. In the discovery set, an expression panel was developed according to the concordance index (C-index) values for overall survival from all 4095 combinations of the 12 candidate molecular markers. Expression scores was determined with weighting according to the coefficient in a Cox regression, and patients were classified into grade 1, 2 and 3. Reproducibility was then tested in the validation set. A panel consisting of four markers, PRMT5, MAGED4, DPYSL3 and AJAP1 was selected as the optimal and most well-balanced set with a C-index value of 0.707. Patient prognosis was clearly stratified by the expression grade using this panel. In the validation set, both overall and disease-free survival rates decreased incrementally with as the grade increased. Higher grades were significantly associated with tumor multiplicity and vessel invasion. The prevalence of extrahepatic recurrences was increased in grade 3 patients. The integrated multigene expression panel clearly stratified HCC patients into low, intermediate and high risk.

DOI： 10.18632/oncotarget.20369

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：BMC Cancer  

Background: Molecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC). In this study, we focused on G protein-coupled receptor 155 (GPR155), a cell surface signaling protein, as a candidate biomarker. Methods: We analyzed GPR155 expression, DNA methylation, and copy number in HCC cell lines. The clinical significance of GPR155 expression was evaluated using 144 pairs of surgically resected liver and normal tissues with subgroup analysis based on hepatitis virus infection. Results: GPR155 mRNA expression levels were differential and were decreased in 89% of HCC cell lines. No DNA methylation was detected, whereas copy number alterations were present in five (56%) HCC cell lines. GPR155 mRNA expression level was independent of background liver status and significantly lower in HCC tissues than corresponding normal liver tissues. The expression patterns of GPR155 protein by immunohistochemical staining were significantly associated with those of GPR155 mRNA. Downregulation of GPR155 was significantly associated with more aggressive HCC phenotypes including high preoperative α-fetoprotein, poor differentiation, serosal infiltration, vascular invasion, and advanced disease stage. Patients with downregulation of GPR155 were more likely to have worse prognosis after curative resection irrespective of hepatitis virus infection. Patients who experienced extrahepatic (distant) recurrences had significantly lower GPR155 expression than those with intrahepatic (liver confined) recurrences. Conclusions: Downregulation of GPR155 may serve as a prognosticator that also predicts initial recurrence sites independent of hepatitis virus infection.

DOI： 10.1186/s12885-017-3629-2

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Oncology Reports  

Breast cancer (BC) is the most common malignant tumor among women worldwide. Development of novel molecular targets is important to improve prognosis of BC patients. Derlin 3 (DERL3) gene is a member of derlin family, and its coding protein is critical to the endoplasmic reticulumassociated degradation mechanism. However, its oncological role in breast cancer remains unclear. This study evaluated DERL3 expression and function in BC. We analyzed DERL3 mRNA in 13 BC and two non-cancerous cell lines, and explored effects of DERL3 knockdown on BC proliferation, invasion and migration. We also evaluated correlation of DERL3 mRNA expression levels with clinicopathological factors and prognosis in 167 BC patients. DERL3 mRNA expression was detected in five (38%) BC cell lines. Inhibiting DERL3 expression significantly decreased proliferation and invasion in BC cells. Specimens from patients with lymph node metastasis had higher DERL3 mRNA expression than those without (P=0.030). Patients in the highest quartile for DERL3 mRNA expression (n=42) were more likely to experience shorter overall survival than other patients (P=0.032). These findings indicate that DERL3 promotes malignant phenotype in BC cells. DERL3 may serve as a potential prognostic marker and therapeutic target for BC.

DOI： 10.3892/or.2017.5800

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：Oncology Letters  

Breast cancer (BC) is the most common malignancy among women. Identifying novel biomarkers to predict prognosis accurately is important in managing this disease. The regulatory factor X1 (RFX1) gene is a member of the regulatory factor X gene family. Its protein reportedly downregulates the proto-oncogene c-myc, but its role in BC has been unclear. In this study, expression and methylation status of RFX1 were determined in BC cell lines. We then evaluated RFX1 mRNA expression levels with regard to clinicopathological factors including postoperative prognosis in 167 patients with BC. Expression of RFX1 was heterogeneous among cell lines, and we found no DNA methylation at the RFX1 promoter region. Patients were categorized into groups with high or low RFX1 expression, based on ratio of RFX1 mRNA expression in BC and adjacent non-cancerous tissues. The high RFX1 group was significantly associated with low T factor (P=0.028), earlier disease stage (P=0.015), positive expression of estrogen receptor (P=0.005) and progesterone receptor (P=0.011), negative expression of human epidermal growth factor receptor 2 (P=0.001). The high RFX1 group experienced more favorable disease-free survival (P=0.007) and overall survival (P=0.013). In multivariate analysis, RFX1 expression was an independent prognostic factor for disease-free survival. Our findings indicate that RFX1 may serve as a prognostic marker for BC.

DOI： 10.3892/ol.2017.6005

Web of Science

Scopus

PubMed