BACKGROUND:Small nucleolar RNA host gene 7 (SNHG7) is a novel identified oncogenic gene in tumorigenesis. However, the role that SNHG7 plays in pancreatic cancer (PC) remains unclear. In this study, we aimed to investigate the functional effects of SNHG7 on PC and the possible mechanism.METHODS:The expression levels of SNHG7 in tissues and cell lines were measured by RT-qPCR. Cell viability, apoptosis, migration and invasion were examined to explore the function of SNHG7 on PC. Bioinformatics methods were used to predict the target genes. The mechanism was further investigated by transfection with specific si-RNA, miRNA mimics or miRNA inhibitor. Tumor xenograft was carried out to verify the effects of SNHG7 in vivo.RESULTS:We found that SNHG7 was overexpressed in both PC tissues and cell lines. High expression level of SNHG7 was correlated with the poor prognosis. SNHG7 knockdown inhibited the proliferation, migration and invasion of PC cells. Moreover, SNHG7 was found to regulate the expression of ID4 via sponging miR-342-3p. Additionally, this finding was supported by in vivo experiments.CONCLUSIONS:LncRNA SNHG7 was overexpressed in PC tissues, and knockdown of SNHG7 suppressed PC cell proliferation, migration and invasion via miR-342-3p/ID4 axis. The results indicated that SNHG7 as a potential target for clinical treatment of PC.

Abstract Background Pancreatic cancer, of which pancreatic ductal adenocarcinoma (PDAC) is one of the most prevalent type, is one of the most malignant tumors, with a 5-year survival rate of about 10%. Pancreatic cancer stem cells play pivotal roles in chemoresistance and recurrence. Long non-coding RNAs (lncRNAs) have been identified as key regulators of the biological progression of various cancers. LncRNAs were found to be associated with cancer stem cells, which are related to chemoresistance. LINC01137 has been reported as an oncogene in oral squamous cell carcinoma, and bioinformatic analysis found it associated with pancreatic cancer stem cells. This study is aim to discover the function and the underlying mechanism of LINC01137 in pancreatic cancer. Results LINC01137 was pancreatic cancer stem cell-associated lincRNA and associated with stem genes. LINC01137 was upregulated in pancreatic cancer tissues and cell lines. Its high expression correlated with poor prognosis. Knockdown of LINC01137 expression reduced pancreatic cancer stemness, chemoresistance, and proliferation. Mechanistically, LINC01137 mostly located in cytoplasm and exerted its biological function by binding to miR-7155-5p to activate the KLF12/PI3K/AKT pathway. KLF12 also promoted LINC01137 expression. LINC01137 and KLF12 were involved in promoting PDAC tumorigenesis. Conclusion Our results suggested that LINC01137 functions as an oncogene in pancreatic cancer and identified its post-transcriptional regulatory mechanisms, which may contribute to targeted therapy for pancreatic cancer.

BACKGROUND:Although a substantial increase in the survival of patients with other cancers has been observed in recent decades, pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases. No effective screening approach exists.METHODS:Differential exosomal long noncoding RNAs (lncRNAs) isolated from the serum of patients with PDAC and healthy individuals were profiled to screen for potential markers in liquid biopsies. The functions of LINC00623 in PDAC cell proliferation, migration and invasion were confirmed through in vivo and in vitro assays. RNA pulldown, RNA immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays and rescue experiments were performed to explore the molecular mechanisms of the LINC00623/NAT10 signaling axis in PDAC progression.RESULTS:A novel lncRNA, LINC00623, was identified, and its diagnostic value was confirmed, as it could discriminate patients with PDAC from patients with benign pancreatic neoplasms and healthy individuals. Moreover, LINC00623 was shown to promote the tumorigenicity and migratory capacity of PDAC cells in vitro and in vivo. Mechanistically, LINC00623 bound to N-acetyltransferase 10 (NAT10) and blocked its ubiquitination-dependent degradation by recruiting the deubiquitinase USP39. As a key regulator of N4-acetylcytidine (ac4C) modification of mRNA, NAT10 was demonstrated to maintain the stability of oncogenic mRNAs and promote their translation efficiency through ac4C modification.CONCLUSIONS:Our data revealed the role of LINC00623/NAT10 signaling axis in PDAC progression, showing that it is a potential biomarker and therapeutic target for PDAC.

Abstract Pancreatic cancer, which most commonly refers to pancreatic ductal adenocarcinoma (PDAC), is one of the most malignant tumors, with a 5-year survival rate of about 4%. Pancreatic cancer stem cells play pivotal roles in chemoresistance and recurrence. Long non-coding RNAs (lncRNAs) have been identified as key regulators of the biological progression of various cancers. Recently, lncRNAs were found to be associated with cancer stem cells, which are related to chemoresistance. LINC01137 has been reported as an oncogene in oral squamous cell carcinoma. However, its function and underlying mechanisms in pancreatic cancer remain unclear. Online datasets were used to screen for cancer stem cell-associated lncRNAs and to confirm the relationship between LINC01137 and stem genes. Quantitative real-time PCR was performed to detect RNA expression. In situ hybridization and nucleocytoplasmic separation were used to determine subcellular location. Direct binding of LINC01137 to miR-7155-5p was verified using a dual-luciferase reporter assay. LINC01137 was upregulated in pancreatic cancer tissues and cell lines. Its high expression correlated with advanced pathological stages and poor prognosis. Induction of LINC01137 expression boosted pancreatic cancer stemness, chemoresistance, and proliferation. Mechanistically, LINC01137 exerted its biological function by binding to miR-7155-5p to activate the KLF12/PI3K/AKT pathway. KLF12 also promoted LINC01137 expression. LINC01137 and KLF12 were involved in promoting PDAC tumorigenesis. Our results suggested that LINC01137 functions as an oncogene in pancreatic cancer and identified its post-transcriptional regulatory mechanisms, which may contribute to targeted therapy for pancreatic cancer.

Pancreatic cancer (PC) is one of the deadliest gastrointestinal cancers, accounting for the fourth highest number of cancer-related fatalities. Increasing data suggests that mesenchymal stem cells (MSCs) might influence the drug resistance of GC cells in the tumor microenvironment and play essential roles in drug resistance development. However, the precise underlying process remains a mystery. The purpose of this study was to look at the control of MSC-induced SNHG7 in pancreatic cancer. In vitro and in vivo sphere formation, colony formation, and flow cytometry investigations revealed the stemness and Folfirinox resistance in pancreatic cancer cells. To confirm the direct connections between SNHG7 and other related targets, RNA pulldown and immunoprecipitation tests were performed. MSC co-culture enhanced the stemness and Folfirinox resistance in pancreatic cancer cells according to the findings. MSC co-culture increased SNHG7 expression in pancreatic cancer cells, contributing to the stemness and Folfirinox resistance. We demonstrated that Notch1 interacted with SNHG7 and could reverse the facilitative effect of SNHG7 on the stemness and Folfirinox resistance in pancreatic cancer cells. Finally, our findings showed that MSCs increased SNHG7 expression in pancreatic cancer cells, promoting the stemness and Folfirinox resistance via the Notch1/Jagged1/Hes-1 signaling pathway. These findings could provide a novel approach and therapeutic target for pancreatic cancer patients.

BACKGROUND:The significance of surgical resection in the treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is currently unclear. This study aimed to summarize and clarify the experience of surgical treatment of M1 PDAC in our center and evaluate whether it may offer benefits to some metastatic PDAC patients.METHODS:We analyzed the data of the patients with M1 PDAC who underwent synchronous tumor resection between 2003 and 2014 at Ruijin Hospital. Simultaneously, clinical data for M1 PDAC patients who underwent palliative bypass or exploratory laparotomy only was also collected during the same period as control. Every patient was followed up at least 3 years after hospitalization. The follow-up endpoint was December 31, 2017.RESULTS:A total of 36 patients underwent synchronous tumor resection; of them, 7 received postoperative adjuvant chemotherapy. Their 1-, 2-, and 3-year survival rates were 27.3%, 21.2%, and 7.1%, respectively, and the overall survival was 7.9 months. The overall survival of the palliative bypass and exploratory laparotomy groups was only 4 and 3.7 months, respectively (P<0.05).CONCLUSIONS:It is unclear whether synchronous tumor resection can benefit M1 PDAC patients due to tumor heterogeneity and differences in tumor burden. However, our current experience indicated that synchronous tumor resection can be safely performed and might be appropriate for some highly selected patients due to the relatively longer survival time. Combined (neo)adjuvant chemotherapy would further prolong overall survival in these patients.

This study aimed to determine the outcome of pancreatic metastatic renal cell carcinoma (PmRCC) after treatment and share the relevent results.

BACKGROUND:Ten-eleven translocation 1 (TET1) is a dioxygenase that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) to induce DNA demethylation. TET1 has been reported to be absent in cancers, and to influence various oncogenes and anti-oncogenes. However the function of TET1 in pancreatic tumor remains poorly understood. In this study, we investigated the role of TET1 in the progression of pancreatic tumor and its mechanism of tumor suppression.METHODS:Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining and dot blot were performed to detect the TET1 and 5-hmC expression in pancreatic tumor tissues and its adjacent non-tumor tissues. The clinical parameters significance of pancreatic tumor tissues was determined statistically. TET1 over-expression and knock-out cell lines were built and confirmed in vitro. Cell proliferation assay, wound-healing assays, transwell migration assay and nude mice model of orthotopic pancreatic cancer implantation were performed to assess the function of TET1 in pancreatic tumor. Western blot, qRT-PCR, immunofluorescence (IF), bisulfate sequencing (BSP), Chromatin immunoprecipitation (ChIP) were used to uncover the mechanism.RESULTS:TET1 levels and 5-hmC content were downregulated in pancreatic tumor tissues and cell lines, and pancreatic tumor patients with low TET1 levels had a shorter overall survival than patients with high levels of TET1. TET1 suppressed pancreatic tumor proliferation and metastasis in vivo and in vitro. TET1 bound to the secreted frizzled-related protein 2 (SFRP2) promoter and catalyzed demethylation to activate transcription of SFRP2, inhibiting both the canonical and non-canonical Wnt signaling pathways, and ultimately obstructing epithelial-mesenchymal transition (EMT) in pancreatic tumors.CONCLUSION:We found TET1 plays as a suppressor in pancreatic tumor progression via obstructing Wnt signaling pathways.

Middle pancreatectomy (MP) is safe and feasible in patients with benign or low-grade malignant tumors located at the neck or proximal body of the pancreas. As a tissue-sparing operation, MP can preserve normal pancreatic function and reduce the risk of postoperative endocrine and exocrine insufficiency. However, the morbidity, especially the postoperative pancreatic fistula (POPF) rate, remains high. A robot-assisted surgical system may provide patients with less trauma; however, there are few reports on robot-assisted middle pancreatectomy (RMP). We describe the experience of RMP at our center to illustrate the learning curve (LC). From August 2010 to July 2017, 100 patients underwent RMP in the Pancreatic Disease Center of Shanghai Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine. Patient characteristics, operative outcomes, and oncological outcomes were collected and analyzed. The CUSUM curve was analyzed according to operative time and estimated blood loss (EBL) and was used to describe the LC and identify the flexion points. Among the 100 patients who underwent RMP in our hospital, the mean age was 47.5 ± 14.2 years, and 69 patients were female. From the CUSUM curve, we found two flexion points: cases 12 and 44. After 44 cases, the rate of improvement was much faster. We separated the patients into two groups based on the LC (cases 1–44 and cases 45–100). There were significant improvements in operative time (173.1 ± 44.7 min vs. 137.3 ± 30.1 min, p < 0.001) and EBL (103.4 ± 90.0 ml vs. 69.3 ± 53.9 ml, p = 0.021). The overall POPF rate was 32% (32/100), while the incidence rate of biochemical leakage was 14% (14/100). However, there was no significant difference in the risk of POPF or other complications between the two groups. The postoperative length of stay (LOS) was also not different. The 90-day mortality rate was 1%. From our long-term follow-up, pancreatic function was preserved in most patients, with only three cases of endocrine insufficiency and two cases of exocrine insufficiency. RMP was helpful and a good choice for the selected patients. PF was the main complication and has not been improved until now. There were two flexion points in the LC at cases 12 and 44. More cases are needed to gain more experience. A larger sample size and prospective studies are needed to verify the advantage of RMP.

Ubiquitin-specific protease 4 (USP4) is a member of the deubiquitinating enzyme family, which plays an important role in human tumor diseases. However, the mechanisms by which USP4 facilitates tumor development, especially in hepatocellular carcinoma (HCC), remain unclear. Clinically, we found that USP4 is overexpressed in human HCC tissues compared with adjacent non-tumoral tissues and is significantly correlated with malignant phenotype characteristics, including tumor size, tumor number, differentiation, serum alpha-fetoprotein level, and vascular invasion. Moreover, Kaplan-Meier survival analysis showed a poor overall survival rate in patients with USP4-overexpressing tumors. Analyses of univariate and multivariate Cox proportional hazard models indicated that USP4 is a prognostic biomarker for poor outcome. Using in vitro and in vivo assays, we demonstrated that USP4 overexpression enhanced HCC cell growth, migration, and invasion. Mechanistically, cyclophilin A (CypA) was identified as an important molecule for USP4-mediated oncogenic activity in HCC. We observed that USP4 interacted with CypA and inhibited CypA degradation via deubiquitination in HCC cells. Subsequently, the USP4/CypA complex activated the MAPK signaling pathway and prevented CrkII phosphorylation. These data suggest that USP4 acts as a novel prognostic marker, offering potential therapeutic opportunities for HCC.

This study investigated the significance of Larelated protein 1 (LARP1) in the development and progression of colorectal cancer (CRC). Quantitative real-time polymerase chain reaction and Western blot analyses were carried out to determine the mRNA and protein expression of LARP1 in CRC tumor tissues and paired adjacent normal mucosa. The expression of LARP1 was upregulated in CRC. Immunohistochemical analysis using tissue microarray was performed. A positive correlation between LARP1 and proliferating cell nuclear antigen (PCNA) in the area of proliferation was observed using the Spearman's correlation coefficient test (r = 0.332, P < 0.01). The elevated expression of LARP1 significantly correlated with T stage (P = 0.02), N stage (P = 0.006), M stage (P < 0.001), American Joint Committee on Cancer (AJCC) stage (P = 0.04), differentiation rank (P < 0.001), and PCNA level (P < 0.001). In addition, the inhibitory effect of LARP1 knockdown on CRC cell proliferation was demonstrated using Cell Counting Kit-8 (CCK8) and colony-forming cell (CFC) assays. Multivariate analysis showed that LARP1 was an independent prognostic factor for overall survival (OS; hazard rate (HR) = 0.244; 95 % confidence interval (CI), 0.078-0.769; P = 0.016) and disease-free survival (DFS; HR = 0.281; 95% CI, 0.086-0.917; P = 0.035) in CRC patients. LARP1 plays an important role in the proliferation of colorectal cancer and represents a new prognostic indicator.