記述言語：日本語   出版者・発行元：Clinical Epigenetics  

Background: Pancreatic cancer is one of the lethal cancers among solid malignancies. Pathological diagnosis of surgical margins is sometimes unreliable due to tissue shrinkage, invisible field cancerization and skipped lesions like tumor budding. As a result, tumor recurrences sometimes occur even from the pathologically negative surgical margins. Methods: We applied molecular surgical margin (MSM) analysis by tissue imprinting procedure to improve the detection sensitivity of tiny cancerous cells on the surgical specimen surface after pancreatoduodenectomy. Surgical specimens were collected from 45 pancreatic cancer cases who received subtotal stomach preserving pancreatoduodenectomy at Nagoya University Hospital during 2017–2019. Quantitative methylation-specific PCR (QMSP) of the original methylation marker panel (CD1D, KCNK12, PAX5) were performed and analyzed with postoperative survival outcomes. Results: Among 45 tumors, 26 cases (58%) were QMSP-positive for CD1D, 25 (56%) for KCNK12 and 27 (60%) for PAX5. Among the 38 tumors in which at least one of the three markers was positive, CD1D-positive cancer cells, KCNK12-positive cancer cells, and PAX5-positive cancer cells were detected at the surgical margin in 8 cases, 7 cases and 10 cases, respectively. Consequently, a total of 17 patients had at least one marker detected at the surgical margin by QMSP, and these patients were defined as MSM-positive. They were associated with significantly poor recurrence-free survival (p = 0.002) and overall survival (p = 0.005) than MSM-negative patients. Multivariable analysis showed that MSM-positive was the only significant independent factor for worse recurrence-free survival (hazard ratio: 3.522, 95% confidence interval: 1.352–9.179, p = 0.010). On the other hand, a significant proportion of MSM-negative cases were found to have received neoadjuvant chemotherapy (p = 0.019). Conclusion: Pancreatic cancer-specific methylation marker panel was established to perform MSM analysis. MSM-positive status might represent microscopically undetectable cancer cells on the surgical margin and might influence the postoperative long-term outcomes.

DOI： 10.1186/s13148-021-01165-8

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記述言語：日本語   出版者・発行元：Contemporary Clinical Trials Communications  

In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating resectable stage II or III esophageal squamous cell carcinoma (ESCC). However, 5-fluorouracil plus cisplatin does not benefit cohorts with clinical stage III ESCC, suggesting the requirement for a more effective regimen. We are conducting a single-arm phase II study to assess the safety and efficacy of neoadjuvant docetaxel, oxaliplatin plus S-1 (DOS) for treating patients with clinical stage III ESCC. The primary endpoint is the pathological response rate, and the target number is 45 patients. Safety, response rate, R0 resection rate, and survival are secondary endpoints. This trial is registered in the Japan Registry of Clinical Trials as jRCTs041210023. We are conducting a prospective phase II trial to evaluate the safety and efficacy of three courses of neoadjuvant DOS treatment followed by radical esophagectomy for clinical stage III ESCC.

DOI： 10.1016/j.conctc.2021.100853

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記述言語：日本語   出版者・発行元：Nagoya Journal of Medical Science  

A 45-year-old female was admitted to the hospital with a diagnosis of acute pancreatitis. A computed tomography scan showed two extrahepatic bile ducts. Magnetic resonance cholangiopancreatography suggested a stone in one of the bile ducts. Endoscopic retrograde cholangiopancreatography revealed two extrahepatic bile ducts joining at the hilum of the liver accompanied with pancreaticobiliary maljunction. Sphincterotomy was performed and a protein plug was drained from the bile duct. Several treatment options were discussed, and the patient was treated with laparoscopic cholecystectomy without extrahepatic bile duct resection and planned to be followed up considering the risk of carcinogenesis in the bile ducts.

DOI： 10.18999/nagjms.83.3.655

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記述言語：日本語   出版者・発行元：In Vivo  

Background/Aim: Hepatocellular carcinoma (HCC) mainly develops in the damaged liver from hepatitis C virus (HCV) or hepatitis B virus (HBV) infection in Japan. On the other hand, the occurrence of HCCs derived from the liver without viral infection has recently been increasing. Our aim was to identify characteristics specific to HCCs with virus-infected liver (HCC-BC) or those with non-B- and non-C-infected liver (HCC-NBNC), Patients and Methods: We collected preoperative serum α-fetoprotein (AFP) and Des-Gamma-Carboxy Prothrombin (DCP), also known as PIVKA-II values from surgically resected HCC cases during 1994-2017 in our department. Results: Preoperative serum AFP values of HCC-BC cases (n=284) were higher compared to HCC-NBNC cases (n=88) (p=0.016), whereas serum DCP values of HCC-NBNC cases were higher compared to HCC-BC cases (p<0.001). Multivariable analyses indicated that abnormal serum AFP [hazard ratio (HR)=1.46, 95% conficdence interval (CI)=1.03-2.07, p=0.035) was one of the significant recurrence-free survival predictors of HCC-BC cases, while abnormal serum DCP (HR=4.99, 95%CI=1.91-13.01, p=0.001) was one of the significant recurrence-free survival predictors of HCC-NBNC cases. Conclusion: HCC-NBNC cases have a different tumor marker profile from HCC-BC cases. Elevated DCP could be both a diagnostic and prognostic marker of HCC-NBNC patients.

DOI： 10.21873/invivo.12434

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記述言語：日本語  

DOI： 10.1158/1538-7445.AM2020-6016

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：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

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oncogene  

Here, we evaluated the therapeutic potential of antibodies (Abs) targeting cholinergic receptor nicotinic beta 2 subunit (CHRNB2) in gastric cancer. To investigate the effects of these Abs on malignant phenotypes in vitro and in mouse xenograft models, we generated gene knockouts through genome editing, performed RNA interference-mediated knockdown of gene expression, and ectopically expressed CHRNB2 in gastric cancer cells. The effects of anti-CHRNB2 Abs on the proliferation of cancer cells were evaluated both in vitro and in vivo. We determined the effects of Chrnb2 deficiency on mice and the clinical significance of CHRNB2 expression in gastric cancer clinical specimens. Knockdown of CHRNB2 attenuated gastric cancer cell proliferation, whereas forced overexpression of CHRNB2 increased cell proliferation. Knockout of CHRNB2 significantly influenced cell survival and functions associated with metastasis. The effects of polyclonal Abs targeting the C- and N-termini of CHRNB2 guided the development of anti-CHRNB2 monoclonal Abs that inhibited the growth of gastric cancer cells in vitro and in vivo. Pathway analysis revealed that CHRNB2 interfered with signaling through the PI3K-AKT and JAK-STAT pathways. Chrnb2-deficient mice exhibited normal reproduction, organ functions, and motor functions. CHRNB2 regulates multiple oncological phenotypes associated with metastasis, and blockade of CHRNB2 expression using specific Abs shows promise for controlling metastasis in gastric cancer.

DOI： 10.1038/s41388-021-01945-9

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Anticancer Research  

Background: Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. Patients and Methods: A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. Results: OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). Conclusion: We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (<2,000 U/ml) as new criteria for defining OM pancreatic cancer.

DOI： 10.21873/anticanres.15189

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nutrition and Cancer  

Background: The Apolipoprotein-related MORtality RISk (AMORIS) study in Sweden revealed that serum uric acid (SUA) was significantly associated with hepatobiliary cancer occurrence. However, the association with postoperative hepatocellular carcinoma (HCC) recurrence has not been reported. Methods: A total of 256 surgically resected HCC patients were included (from January 2003 to December 2017) in this study. Comparisons in terms of clinicopathologic factors and long-term outcomes were made between patients with high SUA (>6.1 mg/dl) at the time of hepatectomy and low SUA. Besides, SUA data at one postoperative year (1POY) of the same cohort were collected and analyzed in the same manner. Results: About 88.8% of tumor relapse sites were the remnant liver. High SUA levels were associated with male and well-differentiated HCCs. Recurrence-free survival (RFS) of high SUA patients was significantly inferior to low SUA patients [median survival time (MST): 22.7 vs. 28.5 mo, P = 0.033], whereas no difference was observed in overall survival (MST: both not reached, P = 0.771). RFS of high SUA patients at 1POY also showed significantly poorer outcomes than low SUA patients (MST: 29.3 vs. 57.0 mo, P = 0.049). Conclusions: High SUA implies a significant risk factor of activating hepatocarcinogenesis. Keeping the SUA level low may be recommended after HCC resections.

DOI： 10.1080/01635581.2020.1779758

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Surgery Today  

Purposes: Owing to recent advances in induction chemo(radio)therapy, patients with unresectable locally advanced pancreatic ductal adenocarcinoma (UR-LA PDAC) are sometimes indicated for conversion surgery (CS). However, the predictors for proceeding to CS are unclear. We investigated the predictive factors for CS, especially at the early stage of induction therapy, and evaluated the impact of CS on the survival. Methods: We analyzed 49 UR-LA PDAC patients retrospectively and investigated the predictive factors for proceeding to CS, including early tumor shrinkage (ETS). ETS in this study was defined as shrinkage of tumors by ≥ 15% at 8–12 weeks after the induction of treatment. Results: CS was performed in 21 patients (43%). In a multivariate logistic regression analysis, ETS was an independent predictive factor for successfully proceeding to CS (P = 0.046). The median overall survival (OS) was not reached in the CS group but was 17.2 months in the non-CS group (P < 0.0001). A multivariate analysis by the Cox proportional hazard model identified CS as the only significant independent determinant of the OS (hazard ratio: 0.26, 95% confidence interval: 0.07–0.94, P = 0.004). Conclusions: ETS by induction therapy is a significant predictor of proceeding to CS among patients with UR-LA PDAC. CS was the only independent prognostic factor for this population.

DOI： 10.1007/s00595-020-02220-2

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oncology Letters  

N6‑methyladenosine (m6A), the most abundant internal RNA modification, serves a critical role in cancer development. However, the clinical implications of m6A in hepatocellular carcinoma (HCC) remain unclear. The present study sought to reveal the potential roles of m6A readers, which recognize m6A, in HCC. A total of 177 HCC and paired non‑cancerous liver tissues from patients who underwent hepatectomy were analysed using quantitative PCR for the expression of m6A readers: YT521‑B homology domain family 1 (YTHDF1) and YT521‑B homology domain family 2 (YTHDF2). The expression levels of both YTHDF1 and YTHDF2 were not significantly different between tumour and non‑cancerous tissues (P=0.93 and P=0.7, respectively). Analysis of the association between clinical features and m6A reader expression revealed that YTHDF1 expression was associated with formation of capsule (P=0.02), whereas low YTHDF2 expression was associated with septal forma‑ tion (P=0.02). Furthermore, high YTHDF1 expression and high YTHDF2 expression were significantly associated with shorter recurrence‑free survival (RFS) [YTHDF1: Mean survival time (MST), 34.0 vs. 19.0 months, P=0.014; YTHDF2: MST, 30.1 vs. 12.9 months, P=0.0032], whereas YTHDF1 and YTHDF2 expression was not significantly associated with overall survival (OS) (YTHDF1: MST, 99.4 vs. 70.2 months, P=0.74; YTHDF2: MST, 98.4 vs. 64.1 months, P=0.28). According to multivariate analysis, serosal invasion [hazard ratio (HR), 2.39; 95% CI 1.30‑4.42; P=0.005), portal vein or hepatic vein invasion (HR, 2.82; 95% CI 1.26‑6.28; P=0.01) and YTHDF2 expression in HCC tissues (HR, 1.85; 95% CI 1.09‑3.15; P=0.02) were identified as significant independent prognostic factors for RFS. α‑fetoprotein (HR, 1.79; 95% CI 1.10‑2.92; P=0.02), serosal invasion (HR, 1.99; 95% CI 1.17‑3.34; P=0.01) and portal vein or hepatic vein invasion (HR, 3.02; 95% CI 1.38‑6.61; P=0.006) were identi‑ fied as significant independent prognostic factors for OS. In conclusion, the present study revealed that high YTHDF2 expression, an m6A reader, in HCC tissues was associated with cancer recurrence.

DOI： 10.3892/ol.2021.12799

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記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Annals of surgical oncology  

BACKGROUND: Reports show miR-23b to be a cancer-related biomarker in various cancer types. Interestingly, it has a dual role of oncogenic and tumor-suppressive functions, depending on the cancer type. This study focused on the unknown association of miR-23b-3p with hepatocellular carcinoma (HCC). METHODS: Expression of miR-23b-3p was measured in nine HCC cell lines and 125 resected human HCC samples by TaqMan microRNA assays. To detect its downstream target, miR-23b-3p mimic and inhibitor constructs were transfected and analyzed. RESULTS: HepG2, a high miR-23b-3p-expressing cell line, was transfected with a miR-23b-3p inhibitor construct, whereas SK-Hep1, a low miR-23b-3p-expressing cell line, was transfected with a mimic construct. Proliferation of HCC cells was activated by miR-23b-3p overexpression and diminished by its knockdown. Then, 125 clinical HCC samples were examined to measure miR-23b-3p expression. Tumor expression of miR-23b-3p was upregulated in 48 cases (38%) and downregulated in 77 cases (62%). The upregulated cases were correlated with elderly patients (P = 0.015). These patients also showed significantly poor overall survival [hazard ratio (HR), 3.10; 95% conflidence interval (CI), 1.57-6.29; P = 0.001] in a multivariate analysis. Furthermore, mitochondrial metabolism-related genes (MICU3 and AUH) were detected as specific binding targets. CONCLUSION: The study showed that miR-23b-3p functions as an oncogenic microRNA in HCC cell lines. Its overexpression in resected HCC tissues was a significant prognostic factor of overall survival. Both MICU3 and AUH may be candidate gene targets of miR-23b-3p.

DOI： 10.1245/s10434-020-09283-y

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Circular RNA (circRNA) is a type of non-coding RNA known to affect cancer-related micro RNAs and various transcription factors. circRNA has promise as a cancer-related biomarker because its circular structure affords high stability. We found using high-throughput sequencing that seven candidate circRNAs (hsa_circ_0041150, hsa_circ_0025624, hsa_circ_0001020, hsa_circ_0028129, hsa_circ_0008558, hsa_circ_0036683, hsa_circ_0058087) were downregulated in HCC. The expression of these circRNAs was examined by quantitative PCR in 233 sets of HCC and matched background normal liver tissues, and correlations between candidate circRNA expression and prognosis were evaluated. The results of quantitative PCR showed that expression of hsa_circ_0041150, hsa_circ_0001020 and hsa_circ_0008558 was significantly lower in HCC than in background normal liver tissues. Kaplan–Meier analysis revealed that low expression of hsa_circ_0001020, hsa_circ_0036683, and hsa_circ_0058087 was associated with poor recurrence-free (RFS) and overall survival (OS) in HCC. Additionally, multivariate analysis revealed that low hsa_circ_0036683 expression was a significant prognostic factor, independent from other clinicopathological features, for inferior RFS and OS. There was no significant association between the expression of these circRNAs and hepatitis B/C status or cirrhosis. This study therefore identified circRNAs as potential prognostic markers for patients who undergo curative surgery for HCC and highlighted hsa_circ_0036683 as the most useful biomarker.

DOI： 10.1038/s41598-021-85237-y

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DOI： 10.21873/anticanres.14812

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DOI： 10.21873/anticanres.14812

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DOI： 10.21873/anticanres.14812

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出版者・発行元：Anticancer Research  

DOI： 10.21873/ANTICANRES.14812

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Pancreas  

Objectives In this study, we retrospectively assessed the feasibility and prognostic efficacy of perioperative chemo(radio)therapy for pancreatic cancer (PC) patients according to age. Methods A total of 556 consecutive patients who underwent curative-intent pancreatectomy for PC between 2000 and 2018 were enrolled. Results Of the 556 patients who underwent resection, 95 (17%) were elderly (age, ≥75 years). Postoperative complications did not significantly differ between the 2 age groups, and postoperative prognoses were also similar (recurrence-free survival [RFS], P = 0.68; overall survival [OS], P = 0.28). In this cohort, 103 patients (19%) underwent preoperative chemo(radio)therapy, and 417 (77%) underwent postoperative chemotherapy. Perioperative therapy was found to be significantly beneficial for younger patients (preoperative therapy: RFS, P = 0.006; OS, P < 0.001; postoperative therapy: RFS, P < 0.001; OS, P < 0.001). Conversely, no significant survival benefit of perioperative therapy was found for the elderly (preoperative therapy: RFS, P = 0.28; OS, P = 0.44; postoperative therapy: RFS, P = 0.77; OS, P = 0.08). Conclusions This study demonstrated that, although perioperative therapy is feasible for selected elderly patients with PC, this approach might not be as beneficial as it is for younger PC patients.

DOI： 10.1097/MPA.0000000000001712

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Hepato-Biliary-Pancreatic Sciences  

Background: This study aimed to evaluate the usefulness of perioperative indocyanine green elimination rate (ICG-K) as a predictive factor of posthepatectomy liver failure (PHLF). Methods: This study enrolled 193 patients who underwent hepatectomy between 2013 and 2019. We analyzed the relationship between estimated ICG-K (ICG-Krem) calculated by the preoperative ICG-K and the residual liver volume ratio, ICG-K at days 1 and 7 after hepatectomy (ICG-Kpod1, ICG-Kpod7), and grade B or C PHLF. Results: Grade B and C PHLF were observed in eight and two patients, respectively. ICG-Krem and ICG-Kpod1 were highly correlated (correlation coefficient [CC] 0.715), and ICG-Krem and ICG-Kpod7 were moderately correlated (CC 0.653). Receiver-operating characteristic curve analyses indicated that ICG-Krem and ICG-Kpod1 had moderate diagnostic value, while ICG-Kpod7 had high diagnostic value (area under the curve 0.703, 0.845 and 0.937, respectively). Multivariate analysis demonstrated that ICG-Kpod7 (relative risk [RR] 26.04, P =.012) and postoperative bile leakage (PBL) (RR 226.0, P <.001) were independent predictive factors for PHLF. PBL induced PHLF in seven patients, respectively. Conclusions: ICG-Krem correlated well with postoperative ICG-K, having moderate accuracy as a predictor of PHLF. However, the clinical relevance of postoperatively measuring ICG-K is limited because PHLF is greatly affected by surgical and postoperative factors.

DOI： 10.1002/jhbp.833

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Anticancer Research  

Background/Aim: N6-Methyladenosine (m6A), the most abundant internal modification of RNA, plays a critical role in cancer development. However, the clinical implications of m6A in hepatocellular carcinoma (HCC) remain unclear. Materials and Methods: We analyzed 177 HCC and paired noncancerous liver tissues from patients who underwent hepatectomy according to global m6A quantification and expression of m6A demethylases fat mass and obesity-associated protein (FTO) and alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5). Results: The global m6A quantification revealed no significant difference between HCC and non-cancerous tissue. The expression of m6A demethylases FTO and ALKBH5, was significantly lower in HCC than in non-cancerous tissues (both p<0.001). Furthermore, low ALKBH5 expression in non-cancerous tissues was significantly correlated with worse recurrence-free survival (median of 16.3 vs. 38.9 months, p=0.001). Conclusion: m6A in HCC and its demethylase in surrounding non-cancerous liver tissues might be involved in inherent mechanisms for HCC development and affect malignant potential after HCC resection.

DOI： 10.21873/anticanres.14690

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Anticancer Research  

Background/Aim: Although our understanding of the molecular mechanisms of gastric cancer (GC) development and progression is steadily deepening, the clinical outcome of GC patients remains inadequate. The identification of molecules associated with GC will help improve prognosis. We aimed to identify the molecules involved in GC progression and metastasis. Materials and Methods: Transcriptome analysis was performed on surgically resected gastric tissue from patients with hepatic metastasis. Fourteen cell lines and 230 pairs of primary GC tissues and their corresponding normal adjacent tissues were included in the mRNA expression analysis. Results: Adhesion molecule with Ig like domain 2 (AMIGO2) was identified as a gene of interest. The levels of AMIGO2 mRNA positively correlated with those encoding FOXC2, NODAL, GEMIN2 and negatively correlated with TFPI2. Patients with high AMIGO2 expression experienced significantly shorter disease-free survival and overall survival. High levels of AMIGO2 were associated with poor prognosis. Conclusion: Patients with GC with high AMIGO2 mRNA levels experienced significantly shorter survival, suggesting that AMIGO2 may serve as a prognostic biomarker for GC.

DOI： 10.21873/anticanres.14694

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Molecular Cancer Therapeutics  

Cancer stem cells (CSC) are highly resistant to conventional chemotherapeutic drugs. YAP1 and STAT3 are the two transcription factors that facilitate the therapeutic resistance and expansion of CSCs. The objective of this study was to understand the cross-talk between YAP1 and STAT3 activities and to determine the therapeutic efficacy of targeting dual CSC-regulating pathways (YAP1 and STAT3) combined with chemotherapy in lung adenocarcinoma. Here, we showed that YAP1 contributes to CSC regulation and enhances tumor formation while suppressing apoptosis. Mechanistically, YAP1 promotes phosphorylation of STAT3 by upregulating IL6. In lung adenocarcinoma clinical specimens, YAP1 expression correlated with that of IL6 (P < 0.01). More importantly, YAP1 and phosphorylated STAT3 (pSTAT3) protein expressions were significantly correlated (P < 0.0001) in primary lung adenocarcinoma as determined by IHC. Immunoblotting of 13 lung adenocarcinoma patient-derived xenografts (PDX) showed that all YAP1-expressing PDXs also exhibited pSTAT3. Additional investigations revealed that chemotherapy resistance and malignant stemness were influenced by upregulating NANOG, OCT4, and SOX2, and the expression of these targets significantly attenuated by genetically and pharmacologically hindering the activities of YAP1 and STAT3 in vivo and in vitro. Therapeutically, the dual inhibition of YAP1 and STAT3 elicits a long-lasting therapeutic response by limiting CSC expansion following chemotherapy in cell line xenograft and PDX models of lung adenocarcinoma. Collectively, these findings provide a conceptual framework to target the YAP1 and STAT3 pathways concurrently with systemic chemotherapy to improve the clinical management of lung adenocarcinoma, based on evidence that these two pathways expand CSC populations that mediate resistance to chemotherapy.

DOI： 10.1158/1535-7163.MCT-20-0024

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Science Signaling  

Disruption of the KEAP1-NRF2 pathway results in the transactivation of NRF2 target genes, consequently inducing cell proliferation and other phenotypic changes in cancer cells. Here, we demonstrated that GULP1 was a KEAP1-binding protein that maintained actin cytoskeleton architecture and helped KEAP1 to sequester NRF2 in the cytoplasm. In urothelial carcinoma of the bladder (UCB), silencing of GULP1 facilitated the nuclear accumulation of NRF2, led to constitutive activation of NRF2 signaling, and conferred resistance to the platinum drug cisplatin. Knockdown of GULP1 in UCB cells promoted tumor cell proliferation in vitro and enhanced tumor growth in vivo. In primary UCB, GULP1 silencing was more prevalent in muscle-invasive UCB compared to nonmuscle-invasive UCB. GULP1 knockdown cells showed resistance to cisplatin treatment. In parallel with decreased GULP1 expression, we observed increased expression of NRF2, HMOX1, and other candidate antioxidant genes in cisplatin-resistant cells. Furthermore, low or no expression of GULP1 was observed in most cisplatin nonresponder cases. Silencing of GULP1 was associated with GULP1 promoter hypermethylation in cell lines and primary tumors, and a high frequency of GULP1 promoter methylation was observed in multiple sets of primary clinical UCB samples. Together, our findings demonstrate that GULP1 is a KEAP1-binding protein that regulates KEAP1-NRF2 signaling in UCB and that promoter hypermethylation of GULP1 is a potential mechanism of GULP1 silencing.

DOI： 10.1126/scisignal.aba0443

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PubMed

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Annals of Surgical Oncology  

Background: This study aimed to explore the impact of serum tumor markers on survival for patients with pancreatic cancer (PC) who received initial systemic therapy (IST) followed by surgery. Methods: Between April 2010 and July 2018, 285 consecutive patients who underwent curative intent surgery for PC were enrolled in the study. The relation between carbohydrate antigen 19-9 and duke pancreatic monoclonal antigen type 2 (DUPAN-2) after IST was analyzed as well as PC prognosis. Results: The study identified 95 patients who underwent systemic chemotherapy with or without radiotherapy as IST from the our prospectively maintained database at the Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan. Survival analysis of the 95 patients showed significant differences in recurrence-free survival (RFS) and overall survival (OS) between the DUPAN-2-normalized (D-normalized) and DUPAN-2-unnormalized (D-unnormalized) groups (median RFS, 24.1 vs. 14.2 months, p = 0.003; median OS, not reached vs. 29.6 months, p = 0.003). In addition, a tendency of differences in survival was observed between the D-normalized and D-unnormalized groups with borderline resectable PC (RFS, 20.1 vs. 14.2 months, p = 0.052; OS, not reached vs. 29.6 months, p = 0.081), and significant differences in survival were observed between the D-normalized and D-unnormalized groups with unresectable PC (RFS, 25.1 vs. 12.1 months, p < 0.001; OS, not reached vs. 11.4 months, p < 0.001). Furthermore, multivariate analysis demonstrated that normalized DUPAN-2 independently predicted survival of resected PC [RFS: hazard ratio (HR) 2.180; 95% confidence interval (CI) 1.16–4.08, p = 0.015; OS: HR 2.806; 95% CI 1.19–6.62, p = 0.018]. Conclusions: During IST, DUPAN-2 normalization may potentially predict prolonged survival for PC patients and optimal timing for conversion surgery in IST.

DOI： 10.1245/s10434-019-07981-w

Web of Science

Scopus

PubMed

記述言語：日本語   出版者・発行元：(一社)日本胃癌学会  

記述言語：日本語   出版者・発行元：(一社)日本胃癌学会  

記述言語：英語   出版者・発行元：(一社)日本胃癌学会  

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Long non-coding RNAs (lncRNAs) were shown to be the crucial regulators of the many diseases. In this study, the expressions of lncRNAs were investigated in resected 158 hepatocellular carcinomas (HCCs) to evaluate the effects of their expression levels on prognosis. The expression levels of HULC and MALAT1 were shown to be significantly higher in the normal background tissue of HCC than those in the normal liver tissue of metastatic liver tumor without hepatitis (HULC: fold change 14.9, P = 1.7e-06; MALAT1: fold change 17.5, P = 1.2e-06. The formation of capsule was shown to be correlated with the increased expression of HULC (P = 0.041), while the size of HCC under 2 cm was correlated with a decrease in MALAT1 expression (P = 0.019). The levels of serum alpha-fetoprotein above 20 ng/mL indicated a decreased expression of both HULC and MALAT1 (HULC: P = 0.017; MALAT1: P = 0.0036). The increase in the expression levels of MALAT1 in HCC tissues was significantly correlated with better overall survival (HULC: P = 0.099, MALAT1: P = 0.028). Thus, the expression of these lncRNAs in HCC potentially correlates with the HCC malignancy and they represent potential prognostic biomarkers of the resected HCC.

DOI： 10.1038/s41598-017-16260-1

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Scopus

PubMed

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oncology Letters  

Gastric cancer (GC) is a leading cause of cancer-related death, particularly in Asia. Epidemiological and other clinical studies have identified an association between a number of risk factors, including Helicobacter pylori, and GC. A number of studies have also examined genetic changes associated with the development and progression of GC. When considering the clinical significance of the expression of a specific gene, its epigenetic modulation should be considered. Epigenetic modulation appears to be a primary driver of changes in gastric tissue that promotes carcinogenesis and progression of GC and other neoplasms. The role of epigenetic modulation in GC carcinogenesis and progression has been widely studied in recent years. In the present review, recent results of epigenetic modulation associated with GC and their effects on clinical outcome are examined, with particular respect to DNA methylation, histone modulation and non-coding RNA. A number of studies indicate that epigenetic changes in the expression of specific genes critically affect their clinical significance and further study may reveal epigenetic changes as the basis for targeted molecular therapy or novel biomarkers that predict GC prognosis or extension of this often fatal disease.

DOI： 10.3892/ol.2017.5912

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Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/or.2017.5541

Web of Science

PubMed

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Anticancer Research  

Background/Aim: Inflammasomes are multiprotein complexes that evoke key inflammatory cascades. The present study evaluated the influence of inflammasome component expression in non-tumorous tissue on postsurgical hepatocellular carcinoma (HCC) prognosis. Materials and Methods: The expressions of candidate genes were investigated using real-time quantitative reverse-transcription polymerase chain reaction in resected HCC cases. In order to identify potential prognostic factors, statistical analyses were performed for each gene. Results: The expression of nod-like receptor family, pyrin domain containing 3 (NLRP3), nod-like receptor family, CARD domain containing 4 (NLRC4), and absent in melanoma 2 (AIM2) was significantly higher in corresponding normal tissue (CN) compared to those in HCC. High expression of NLRP3, NLRC4, and caspase 1 (CASP1) in CN was significantly correlated with worse overall survival. Furthermore, multivariate analysis revealed that NLRP3 expression in CN greater than the median was an independent prognostic factor for poorer overall survival. Conclusion: High expression of NLRP3, NLRC4, and CASP1 in background non-tumorous liver is significantly correlated with poor prognosis of patients after resection of HCC.

DOI： 10.21873/anticanres.11320

Web of Science

Scopus

PubMed

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：英語   出版者・発行元：(一社)日本胃癌学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本膵臓学会  

記述言語：日本語   出版者・発行元：(一社)日本膵臓学会  

記述言語：日本語   出版者・発行元：日本消化器病学会-東海支部  

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

記述言語：日本語   出版者・発行元：(一社)日本胃癌学会  

記述言語：日本語   出版者・発行元：(一社)日本胃癌学会  

記述言語：日本語   出版者・発行元：(一社)日本消化管学会  

記述言語：日本語   出版者・発行元：(一社)日本内視鏡外科学会  

記述言語：日本語   出版者・発行元：(一社)日本内視鏡外科学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：日本語   出版者・発行元：日本消化器病学会-東海支部  

記述言語：日本語   出版者・発行元：日本消化器病学会-東海支部  

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：日本語   出版者・発行元：日本臨床外科学会  

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：日本語   出版者・発行元：(一社)日本外科学会