Antitumor Effect of Galectin-9 on Cell Proliferation and Tumor Growth of Human Duodenal Adenocarcinoma Cells.

BACKGROUND/AIM: Galectin-9 (Gal-9) induces tumor cell apoptosis in lymphoma and other malignant cell types. Duodenal adenocarcinoma is a rare malignancy, and there are insufficient data to determine a standard therapeutic approach. Here, we investigated the antitumor effect of Gal-9 in HuTu-80 duodenal adenocarcinoma cells. MATERIALS AND METHODS: Cell proliferation was examined in HuTu-80 cells using a Cell Counting Kit-8 assay. Cell cycle analysis, apoptosis array, and microRNA expression analysis were performed to identify the effect of Gal-9 on HuTu-80 cells. The antitumor effect of Gal-9 was also examined using xenograft mouse models. RESULTS: Gal-9 suppressed the proliferation of HuTu-80 via blockade of the G0 to G1 cell cycle transition. This blockade was accompanied by a strong decrease in cyclin D1 and phosphorylated Rb, suggesting a G1 arrest. Additionally, Gal-9 induced apoptosis, and the expression of cleaved caspase-3 was increased in Gal-9-treated HuTu-80 cells according to the apoptosis array. MiRNA microarrays revealed that Gal-9 altered the expression of miRNAs in HuTu-80 cells. CONCLUSION: These data demonstrate the therapeutic potential of Gal-9 and provide molecular mechanistic insights into its antitumor effect in HuTu-80 cells.

Validation of fatty liver index as a predictor of hepatic steatosis in Asian populations: Impact of alcohol consumption and sex.

AIM: This study was undertaken to investigate the utility of the fatty liver index (FLI) as a noninvasive tool for predicting hepatic steatosis based on alcohol consumption and sex in a large Asian population. METHODS: We carried out a single-center observational cohort study at the HITO Medical Center in Japan and enrolled 1976 Asian subjects. The subjects were categorized into nondrinkers and light drinkers (0-19 g/day) and moderate drinkers (20-59 g/day) based on their self-reported alcohol intake. We used physical examinations, laboratory tests, and a questionnaire to collect information on various factors related to the FLI, including body mass index, waist circumference, and levels of γ-glutamyl transferase and triglycerides. RESULTS: The diagnostic accuracy of the FLI was assessed by calculating the area under the receiver operating characteristic curve (AUROC), and optimal cut-off values were determined using Youden's index. The FLI had an acceptable performance index of >0.7 both overall and in all subgroups, with an overall AUROC of 0.844. The AUROCs were higher in women and moderate drinkers of both sexes. We also compared the cut-off values obtained in the present study with the previously reported values of 30 and 60. Optimal cut-off values for the FLI were calculated for the total population and subgroups and were found to differ from the previously established values in other countries. CONCLUSIONS: Our study suggests that the FLI is a useful noninvasive marker for predicting hepatic steatosis in a large Asian population, irrespective of alcohol consumption and sex.

Influence of diabetes mellitus and effectiveness of metformin on hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers, and it is important to elucidate the carcinogenic factors and improve the recurrence and prognosis of HCC patients. Diabetes mellitus (DM) has been reported to be a risk factor for the carcinogenesis of many cancers including HCC, and the mechanism of DM for carcinogenesis is gradually being elucidated. Metformin, a drug for DM, has been reported to have anticancer effects on many cancers, including HCC. Metformin not only suppresses carcinogenesis but also improves the prognosis of recurrence after treatment, and there are many reports on the mechanism of these effects. In this review, we describe the mechanism of action of hyperglycemia and hyperinsulinemia on carcinogenesis by DM against HCC. The carcinogenic effects of DM on hepatitis B, hepatitis C, and nonalcoholic fatty liver disease by etiology are also described. In addition, the carcinogenic effect of metformin on HCC and its mechanism of action are reviewed. We also discuss the effects of metformin on recurrence after hepatectomy and radiofrequency therapy and the effects of metformin in combination with anticancer medicine, focusing on the inhibition of HCC development.

Use of endoscopic gallbladder stenting and biliary scintigraphy for diagnosis of gallbladder dyskinesia: a case report.

A 40-year-old woman visited our hospital with a several-year history of right hypochondriac pain and vomiting after eating. She had been treated for functional dyspepsia, with no improvement in her symptoms. No gallstones were detected on imaging tests, but papillary insufficiency or dyskinesia of the gallbladder was suspected and biliary scintigraphy was performed. Biliary scintigraphy showed delayed excretion of radionuclides from the gallbladder and bile ducts into the duodenum. We initially suspected papillary dysfunction and performed endoscopic sphincterotomy, but there was no improvement in her symptoms. Biliary scintigraphy also showed delayed excretion of radionuclides, especially stagnation of radionuclides in the gallbladder. We suspected gallbladder dyskinesia and performed endoscopic gallbladder stenting, after which her symptoms disappeared and biliary scintigraphy showed improved excretion of radionuclides into the duodenum. Endoscopic gallbladder stenting may be useful for the diagnosis of gallbladder dyskinesia and for determining the efficacy of cholecystectomy.

Effect of Aspirin on G0/G1 Cell Cycle Arrest and microRNA Signatures in Pancreatic Adenocarcinoma Cells.

BACKGROUND/AIM: Anti-inflammatory drugs, such as aspirin, have attracted attention as anticancer agents that can be applied to standard chemotherapy for pancreatic cancer. This study aimed to examine the antitumour effects and possible fundamental mechanisms of aspirin in pancreatic cancer cells. MATERIALS AND METHODS: We appraised the antitumour effects of aspirin on cell proliferation and tumour growth, cell cycle distribution, apoptosis, signalling pathways, angiogenesis-related proteins, and phosphorylated receptor tyrosine kinases (p-RTKs) and identify miRNAs associated with its antitumour effects. RESULTS: Aspirin inhibited cell proliferation in pancreatic cancer cell lines and induced G0/G1 cell cycle arrest by decreasing the expression of cyclin D1. Aspirin inactivated glycogen synthase kinase (GSK)-3ß but had no effect on the p38 mitogen-activated protein kinase (MAPK) pathway, p-RTKs, or angiogenesis-related molecules. Aspirin treatment statistically increased the expression of 274 miRNAs in PANC-1 cells and 30 miRNAs in PK-8 cells and suppressed the expression of 294 miRNAs in PANC-1 cells and 13 miRNAs in PK-8 cells. CONCLUSION: Aspirin inhibited the proliferation of pancreatic cancer cells and induced cell cycle arrest. Aspirin also inactivated GSK-3ß but not the p38 MAPK pathway. Thus, aspirin may be used in combination with chemotherapeutic agents for pancreatic cancer.

Cholecystocolic fistula closed using endoscopic therapy alone: A case report.

BACKGROUND: Cholecystocolic fistula (CCF) is a known but rare complication of cholelithiasis. Treatment for CCF is generally surgical. As the number of elderly patients has increased in recent years, many cases require non-surgical treatment; therefore, endoscopic treatment has gained importance. PATIENT CONCERNS AND DIAGNOSIS: An 87-year-old woman presented with impaired consciousness and symptoms of anorexia. Computed tomography showed cholecystitis and a fistula between the gallbladder and transverse colon. Colonoscopy revealed a CCF. The condition was diagnosed as CCF caused by acute cholecystitis. INTERVENTIONS AND OUTCOMES: The patient declined surgery due to her age. Endoscopic fistula closure was performed using a through-the-scope clip after endoscopic naso-gallbladder drainage. Successful closure of the fistula resulted in improvement of cholecystitis and anorexia. The patient was discharged after one month. It has been more than 18 months since the procedure, there has been no recurrence. CONCLUSION: This report on successful endoscopic closure of a CCF indicates that it may be useful for patients who decline surgery.

Cytomegalovirus colitis with a new diagnosis of ulcerative colitis in an elderly woman.

Objectives: Cytomegalovirus (CMV) colitis is generally diagnosed in immunocompromised patients. It is rare for patients who are not immunocompromised to develop CMV colitis. Cases of CMV colitis in patients with inflammatory bowel disease have also been reported. We encountered a case of CMV colitis with a new diagnosis of severe ulcerative colitis and demonstrated the importance of suspecting ulcerative colitis in immunocompetent patients with CMV colitis. Patient: A 78-year-old woman was hospitalized with fever and diarrhea that had lasted for a month. Colonoscopy revealed continuous diffuse edema, mucosal redness, and multiple punched-out ulcers with bleeding, suggesting cytomegalovirus (CMV) colitis, although she was not immunocompromised. Immunohistochemical staining revealed CMV-positive cells, and CMV colitis was diagnosed. One month later, a colonoscopy was conducted owing to persistent symptoms despite initiating the prescribed antiviral drug. A complete loss of vascular pattern, easy bleeding of the crude mucosa, and exacerbation of multiple punched-out ulcers were observed. She was diagnosed with severe ulcerative colitis. The symptoms of ulcerative colitis disappeared with prednisolone and 5-amino salicylic acid treatment. Conclusion: Ulcerative colitis should be suspected in immunocompetent patients with CMV colitis.

Comparison of plastic stent versus metal stent in preoperative biliary drainage for pancreatic head cancer with neoadjuvant chemoradiotherapy.

BACKGROUND: While neoadjuvant chemotherapy and chemoradiotherapy (NACRT) for pancreatic head cancer are effective, preoperative endoscopic biliary drainage (EBD) is necessary for managing obstructive jaundice and cholangitis during the preoperative waiting period. Nevertheless, ideal choice of stent type is unclear. We compared plastic stents (PS) and metal stents (MS) in these situations. METHODS: We retrospectively studied 43 patients who successfully underwent preoperative EBD prior to NACRT for pancreatic head cancer at a single institution. We divided patients into PS (n = 22) and MS (n = 21) groups. The primary outcome was the rate of re-interventional drainage rate before surgery. Secondary outcomes were rates of EBD-associated and postoperative complications and total costs in the pre- and perioperative periods. RESULTS: The re-intervention rate was significantly greater in the PS group than in the MS group (95% vs 4.8%, respectively, P < 0.05). EBD-associated and postoperative complications were significantly less common in the MS group (P < 0.05). The average total preoperative medical costs were significantly lower in the MS group (PS vs MS: 528,597 vs 395,891 JPY, P = 0.004). CONCLUSIONS: MS can be the first choice for EBD in patients undergoing NACRT for pancreatic head cancer. MS may be less costly overall.

A case report of granulocyte colony-stimulating factor-producing hepatocellular carcinoma that recurred after long-term complete response.

The granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates cell proliferation and differentiation of precursor cells in the bone marrow. Several cases of G-CSF-producing malignant tumors in various organs have been reported, but there are only nine cases of G-CSF-producing hepatocellular carcinoma (HCC) reported in the English literature. G-CSF-producing tumors grow rapidly and have a high probability of distant metastases; thus, they generally have a poor prognosis. Given that the mechanism of the carcinogenesis of G-CSF-producing HCC remains unclear, an efficient treatment strategy also remains to be elucidated. We report herein a case of G-CSF-producing HCC accompanied by leukocytosis and high serum G-CSF concentrations in the disease progression stage after long-term complete response. We also reviewed previous reports to investigate the clinical behaviors of G-CSF-producing HCC, including our case. Clinicians should consider G-CSF-producing HCC in patients with a hepatic mass and drastic leukocytosis, without any evidence of infection and blood disorders. Early diagnosis and prompt therapy, including radical resection, may provide a more favorable prognosis.

Antihypertensive drug telmisartan suppresses the proliferation of gastric cancer cells in vitro and in vivo.

Gastric cancer is one of the most common malignancies diagnosed worldwide. Telmisartan, an angiotensin receptor blocker (ARB), suppresses the proliferation of cancer cells and the growth of tumors through an unknown mechanism. To identify the mechanism, the present study was designed to evaluate the effects of telmisartan on gastric cancer cell lines and tumors in vitro and in vivo and the associated signaling molecules were identified. It was shown here that telmisartan suppressed the proliferation of the cultured human gastric cancer cell lines MKN74, MKN1 and MKN45 as detected in the CCK­8 assay. In a mouse xenograft model of gastric cancer, telmisartan suppressed tumor growth by arresting the cell cycle at the G0/G1 phase through inhibition of the expression of cyclin D1, the catalytic subunit of cyclin dependent kinase 4 (CDK4), as well as the phosphorylation of the tumor suppressor retinoblastoma (pRb) protein as detected by western blotting. Notably, telmisartan did not induce apoptosis, as indicated by consistent levels of caspase­cleaved keratin 18 in MKN74 cells. Furthermore, telmisartan inhibited the phosphorylation of epidermal growth factor receptor (EGFR) and increased the levels of the angiogenesis­related protein tissue inhibitor of metalloproteinase­1 (TIMP­1). Analyses of microarrays revealed that telmisartan altered the expression of miRNAs in MKN74 cells. In conclusion, telmisartan suppressed the proliferation of human gastric cancer cells by inducing cell cycle arrest.

Metformin Inhibits Proliferation and Tumor Growth of QGP-1 Pancreatic Neuroendocrine Tumor Cells by Inducing Cell Cycle Arrest and Apoptosis.

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (pNETs) are rare pancreatic neoplasms, and therapeutic options for pNETs are limited. Metformin is an anti-hypoglycemic drug that appears to have anticancer effects. However, little is known about the effect of metformin on pNETs. In this study, we investigated the anti-proliferative effect of metformin on a human pNET cell line. MATERIALS AND METHODS: The anti-proliferative properties of metformin were evaluated in QGP-1 and NCI-H727 cells using a cell counting kit-8 assay. Xenograft mouse models were used to assess the tumor effect in vivo. RESULTS: Metformin inhibited the proliferation and anti-tumor growth of QGP-1 cells, accompanied by their arrest during the cell cycle at the G0/G1 phase. Immunohistochemical analysis of tumor tissues revealed down-regulation of cyclin D1 and proliferating cell nuclear antigen in the metformin-treated group. Additionally, metformin induced apoptosis, and the expression of survivin and claspin were decreased in metformin-treated QGP-1 cells according to the apoptosis array. Furthermore, the angiogenic related protein TIMP-1 was down-regulated, and its miRNA expression was altered by metformin in QGP-1 cells. CONCLUSION: Taken together, our study demonstrated the therapeutic potential of metformin and provides molecular mechanistic insights into its anti-tumoral effect on pNETs. This study is the first one describing anti-tumoral effects in pNETs.

Role of microRNA-210-3p in hepatitis B virus-related hepatocellular carcinoma.

Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002-2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC.NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.

Anti-diabetic drug metformin inhibits cell proliferation and tumor growth in gallbladder cancer via G0/G1 cell cycle arrest.

Gallbladder cancer is the most common biliary tract cancer with poor prognosis and wide variation in incidence rates worldwide, being very high in some countries in Latin America and Asia. Treatment of type 2 diabetes with metformin causes a reduction in the incidence of cancer. Till date, there are no reports on the anti-tumor effects of metformin in gall bladder cancer. Therefore, this study evaluated the effects of metformin on the proliferation of human gallbladder adenocarcinoma cells in vitro and in vivo, as well as explored the microRNAs associated with the anti-tumor effects of metformin. Metformin inhibited the proliferation in gallbladder adenocarcinoma cell lines NOZ, TGBC14TKB, and TGBC24TKB, and blocked the G0 to G1 transition in the cell cycle. This was accompanied by strong reduction in the expression of G1 cyclins, especially cyclin D1 and its catalytic subunits including cyclin-dependent kinase 4, and in retinoblastoma protein phosphorylation. In addition, metformin reduced the phosphorylation of receptor tyrosine kinases, especially Tie-2, ALK, PYK, EphA4, and EphA10, as well as angiogenesis-related proteins, including RANTES, TGF-ß, and TIMP-1. Moreover, metformin also markedly altered microRNA expression profile leading to an anti-tumor effect. Treatment of athymic nude mice bearing xenograft tumors with metformin inhibited tumor growth. These results suggest that metformin may be used clinically for the treatment of gallbladder adenocarcinoma.

Long-Term Management of Recurrent Cholecystitis after Initial Conservative Treatment: Endoscopic Transpapillary Gallbladder Stenting.

Background: Endoscopic transpapillary gallbladder stenting (ETGBS) is an effective procedure for treating high-risk patients with acute cholecystitis and severe comorbidities. However, the efficacy of ETGBS for recurrent cholecystitis (RC) remains unclear. This study aimed to explore its efficacy in patients with RC for whom cholecystectomy is contraindicated because of its high surgical risk. Methods: Data on 19 high-risk patients who had undergone ETGBS for RC after initial conservative therapy in our institution between June 2006 and May 2012 were retrospectively examined. The primary outcome was the clinical success rate, which was defined as no recurrences of acute cholecystitis after ETGBS until death or the end of the follow-up period. Secondary outcomes were technical success rate and adverse events (AEs). Results: The clinical success rate of ETGBS was 100%, the technical success rate 94.7%, and AE rate 5%: one patient developed procedure-related mild acute pancreatitis. The clinical courses of all patients were as follows: four died of nonbiliary disease, and the remaining 15 were subsequently treated conservatively. The median duration of follow-up was 14.95 months (range 3-42 months). Conclusions: ETGBS is an effective alternative for managing RC in high-risk patients with severe comorbidities.

MicroRNA profiles during galectin-9-induced apoptosis of pancreatic cancer cells.

Pancreatic cancer is the eighth-leading cause of cancer-associated mortality in males and the ninth-leading cause in females worldwide. Even when diagnosed early enough to be potentially resectable, the prognosis of invasive pancreatic cancer is poor. Galectin-9 (Gal-9) is a tandem-repeat type galectin that has recently been demonstrated to possess an anti-proliferative effect on cancer cells. Therefore, the present study evaluated the effects of Gal-9 on the proliferation of human pancreatic cancer cells and examined the microRNAs that are associated with the antitumor effects of Gal-9. Gal-9 suppressed the proliferation of multiple pancreatic cancer cell lines. In addition, Gal-9 treatment increased the levels of caspase-cleaved keratin 18 and the expression of cytochrome c in pancreatic cancer cell lines. This data suggests that Gal-9 induces intrinsic apoptosis in pancreatic cancer cell lines through the caspase-dependent and caspase-independent pathways. In addition, Gal-9 reduced the expression levels of phosphorylated epidermal growth factor receptor and numerous receptor tyrosine kinases (RTKs). In conclusion, Gal-9 may suppress the growth of human pancreatic cancer cells in vitro. These findings suggest that Gal-9 may be a new therapeutic agent for the treatment of pancreatic cancer.