Zhiming Zhao

SOX10 is a novel oncogene in hepatocellular carcinoma through Wnt/β-catenin/TCF4 cascade

SOX (high mobility group) genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the function role of SOXs in the human hepatocellular carcinoma (HCC). The gene expression changes of SOXs in HCC tissues compared with those in noncancerous hepatic tissues were detected using real-time quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) analysis and immunohistochemistry. In addition, we identified the gene SOX10 that was significantly upregulated in HCC by QRT-PCR analysis and immunohistochemistry. Furthermore, we discovered that SOX10 promoted cancer cell proliferation in vitro, and SOX10 expression correlated with elevated β-catenin levels in HCC, and β-catenin function was required for SOX10’s oncogenic effects. Mechanistically, SOX10 facilitates TCF4 to bind to β-catenin and form a stable SOX10/TCF4/β-catenin complex and trans-activate its downstream target gene. SOX10 mutations that disrupt the SOX10-β-catenin interaction partially prevent its function in tumor cells. All in all, SOX10 is a commonly activated tumor promoter that activates Wnt/β-catenin signaling in cancer cells of HCC.

Linc-ROR confers gemcitabine resistance to pancreatic cancer cells via inducing autophagy and modulating the miR-124/PTBP1/PKM2 axis.

PurposeIn this study, we investigated the regulation of linc-ROR on autophagy and gemcitabine resistance of pancreatic cancer cells and further studied the underlying involvement of the miR-124/PTBP1/PKM2 axis in this regulation.MethodsPancreatic cancer cell lines PANC-1 and MIAPaCa-2 cells were used as in vitro model. Autophagy was assessed by western blot of LC3 I/II and observation GFP-LC3 puncta. Cell viability was examined using CCK-8 assay. Cell apoptosis was examined by flow cytometric analysis of Annexin V/PI staining. QRT-PCR, RNA fluorescence in situ hybridization and dual luciferase assay were used to study the expression and the binding between linc-ROR and miR-124.ResultsLinc-ROR siRNA significantly sensitized PANC-1 and MIAPaCa-2 cells to gemcitabine, while linc-ROR overexpression significantly reduced the sensitivity. Linc-ROR knockdown reduced basal autophagy, while linc-ROR overexpression markedly increased basal autophagy in the cells. Linc-ROR siRNA showed similar effect as 3-MA on enhancing gemcitabine-induced cell apoptosis and also reduced PKM2 expression. MiR-124 overexpression restored PKM1 and reduced PKM2 levels in the cells. In addition, miR-124 mimics also alleviated autophagy in pancreatic cancer cells. Both miR-124 mimics and PKM2 siRNA enhanced gemcitabine-induced cell apoptosis. In both pancreatic cell lines and PADC tissues, linc-ROR is negatively correlated with miR-124 expression. In addition, dual luciferase assay verified two 8mer binding sites between miR-124 and linc-ROR.ConclusionLinc-ROR confers gemcitabine resistance to pancreatic cancer cells at least partly via inducing autophagy. There is a linc-ROR/miR-124/PTBP1/PKM2 axis involved in regulation of gemcitabine resistance in pancreatic cancer cells.

Predictive Role of Glutathione-S-transferase Gene Polymorphisms in Risk and Prognosis of Hepatocellular Carcinoma

AIM We conducted a prospective study in an Chinese population to detect associations of GSTM, GSTT and GSTP polymorphisms with hepatocellular carcinoma (HCC), and analyze roles in determining survival outcome. METHODS A prospective follow-up study was conducted with 476 HCC patients and 481 controls collected from May 2005 to May 2007. All patients were followed up until the end of Dec. 2011. GSTM1, GSTT1 and GSTP1 genotyping were performed by PCR-CTPP methods. RESULTS Null GSTM1 carriers had a 1.64 fold risk of HCC compared with non-null genotype, while GSTP1 Val/Val carriers had a 93% increased risk over the GSTP1 IIe/IIe genotype. The median follow-up time for the 476 patients was 34.2 months (range: 1 to 78 months). Individuals with null GSTM1 genotype had better survival of HCC than non-null genotype carriers (HR=0.71, 95%CI=0.45-0.95). Similarly, GSTP1 Val/Val genotypes had significant better survival than the GSTP1 IIe/IIe genotype (HR=0.34, 95%CI=0.18-0.65). Individuals carrying null GSTM1 and GSTP1 Val/Val who received chemotherapy had lower risk of death from HCC than those without chemotherapy. CONCLUSION This study indicated carriage of null GSTM1 and GSTP1 Val/Val genotypes to have roles in susceptibility to and survival from HCC.

Robotic versus laparoscopic distal pancreatectomy: A propensity score-matched study.

Robotic distal pancreatectomy (RDP) is considered a safe and feasible alternative to laparoscopic distal pancreatectomy (LDP). However, previous studies have some limitations including small sample size and selection bias. This study aimed to evaluate whether the robotic approach has advantages over laparoscopic surgery in distal pancreatectomy.

RETRACTED ARTICLE: Transforming growth factor β receptor signaling restrains growth of pancreatic carcinoma cells

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant. Efficient control of cancer growth may substantially improve the survival of PDAC patients. However, no efficient treatments are so far available. Here, we inhibited transforming growth factor β (TGFβ) receptor signaling by overexpression of a key inhibitor of this pathway, SMAD7, in the mouse pancreas, using a recently developed intraductal infusion method. Overexpression of SMAD7 significantly increased growth of both implanted PDAC and PDAC by K-ras modification. Our data thus suggest that TGFβ receptor signaling restrains growth of PDAC, and modulation of TGFβ receptor signaling may be an effective treatment for PDAC.

Comment on Han L et al.: Prognostic value of circulating tumor cells in patients with pancreatic cancer: a meta-analysis

Dear Editor We read with great interests on the recent paper by Han L et al. “Prognostic value of circulating tumor cells in patients with pancreatic cancer: a meta-analysis” published online in Tumor Biology [1]. The investigators (Han L et al.) performed a metaanalysis of nine cohort studies to assess the prognostic value of circulating tumor cells (CTC) in patients with pancreatic cancer. They concluded that CTC-positive pancreatic cancer patients may have worser progression free survival (PFS) and overall survival (OS) than CTC-negative patients. Detection of CTC in peripheral blood may be a promising biomarker for the detection and prognosis of pancreatic cancer. It is the first comprehensive meta-analysis of all eligible studies concerning the prognostic role of CTC in patients with pancreatic cancer. Nevertheless, we have several queries which we would like to communicate with the investigators.

Single-port Retroperitoneoscopic Pancreatectomy Preliminary Results From the First 3 Patients

To date, single-port laparoscopic pancreatic surgery has been rarely reported. This study aimed to evaluate the feasibility and safety of single-port retroperitoneoscopic pancreatectomy based on the first 3 cases in a single center. Three patients with suspected lesions in the distal pancreas underwent single-port retroperitoneoscopic pancreatectomy using a conventional retroperitoneoscopic pancreatectomy approach. All operations were successfully completed utilizing a single port. Operating times were 50, 90, and 150 minutes for the 3 cases. There were no complications, and all patients were discharged within 7 days after surgery. In conclusion, for selected patients, single-port retroperitoneoscopy can be safely utilized for pancreatectomy.

Expression of Ku86 and Presence of Ku86 Antibody as Biomarkers of Hepatitis B Virus Related Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) is a common disease and the third leading cause of cancer-related deaths worldwide. Level of the 82-kDa ATP-dependent DNA helicase II (Ku86) increases in some tumors, but its clinical use as a marker for HCC is rare.AimsTo examine the relationship between increases in Ku86 and the development of hepatitis B virus (HBV)-related HCC to define the relationship between Ku86 and HCC.MethodsExpression of Ku86 in tumor tissue, para-tumor tissue, and normal tissue was examined by immunohistochemistry, and Ku86 antibody titers in patient serum collected pre- and post-operatively were measured by ELISA. Long-term survival of the patients was also monitored.ResultsKu86 staining in tumors was much stronger than in para-tumor and normal tissues. The expression of Ku86 was related to the tumor size, TNM stage, and tumor differentiation but not to gender, age, Child–Pugh score, tumor number, or α-fetoprotein levels. The long-term survival of patients with low Ku86 expression was longer. Patients with HCC had higher pre-operative Ku86 antibody levels. After surgical intervention, Ku86 antibody levels in patients with HCC declined significantly. Survival analysis showed that double-positive patients had the lowest survival rate, double-negative patients had the highest. Receiver operating characteristic curve analysis showed no significant difference between the AFP and Ku86 antibody. Multivariate analysis showed that Ku86 protein and Ku86 antibodies were independent prognostic factors of overall survival.ConclusionsKu86 and Ku86 antibodies are promising tumor markers for early detection and prognosis prediction of HBV-related HCC.

Augmented TGFβ receptor signaling induces apoptosis of pancreatic carcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant tumor in humans. Thus, understanding the tumorigenesis of PDAC appears to help develop efficient therapy. Here, we show that activated TGFβ receptor signaling induces apoptosis of pancreatic carcinoma cells in vitro and in vivo, suggesting that activation of TGFβ receptor signaling may prevent development of PDAC.

Robotic resection of benign nonadrenal retroperitoneal tumors: A consecutive case series

BACKGROUND The deep location, narrow operative space and proximity to major vessels make minimally invasive resection of nonadrenal retroperitoneal tumors (NTRs) challenging and rarely reported. This study aimed to evaluate the safety and feasibility of robotic resection of benign nonadrenal retroperitoneal tumors. METHODS The demographics and perioperative outcomes of a consecutive series of patients who underwent robotic NTR resection between January 1, 2015, and August 30, 2017, were analyzed. RESULTS Twenty-five patients (9 men and 16 women; mean age, 50.5 years) were included in the study. The mean largest tumor diameter was 4.9 cm, 11 had a tumor larger than 5 cm and 13 had a tumor adherent to major vessels. The mean operative time was 139.0 min, and the median estimated blood loss was 50.0 mL (interquartile range, 30-80 mL). No patients required conversion to laparotomy or blood transfusion. Postoperative morbidities occurred in 3 patients (12%), and all recovered after conservative treatment. The mean postoperative hospital stay was 4.8 days. On histopathological examination all the tumors were benign: lymphangioma (8, 32%), schwannoma (5, 20%), lymphatic cyst (4, 16%), paraganglioma (2, 8%), bronchogenic cyst (2, 8%), mucinous cystadenoma (1, 4%), neurofibroma (1, 4%), ganglioneuroma (1, 4%), and Castleman disease (1, 4%). Neither large tumor size nor adherence to major vessels affected the perioperative outcomes. CONCLUSIONS Robotic resection of NRTs is safe and feasible even for tumors which were large or adherent to major vessels.