Kaiming Leng

Impact of Pancreatic Margin Status and Lymph Node Metastases on Recurrence after Resection for Invasive and Noninvasive Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Meta-Analysis

Background: Accurate information is currently lacking regarding the values of positive margins (M+) and lymph node (LN) metastases as independent predictors of postoperative recurrence in invasive and noninvasive intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Methods: A comprehensive online literature search identified all types of primary studies that included M+ and LN metastases as risk factors and defined recurrence as an outcome in patients with IPMNs. Suitable articles were also identified by manually researching references in qualifying articles. A meta-analysis of the result was performed using a random effects model. Results: The recurrence rate in noninvasive IPMNs was 3.72% in patients with negative margin (M–) versus 9.56% in those with M+ (odds ratio, OR = 0.37, 95% confidence interval, 95% CI: 0.17–0.78, p = 0.010). The recurrence rate in invasive M– IPMNs in was 33.85% compared to 53.66% in M+ IPMNs (OR = 0.47, 95% CI: 0.25–0.88, p = 0.020). The recurrence rate in invasive IPMNs with positive LN was 76.92% compared to 30.86% with negative LN; OR = 0.15, 95% CI: 0.06–0.37, p < 0.0001). Conclusions: M+ were associated with disease recurrence in all patients with IPMN, and nodal metastases were significantly associated with recurrence in invasive IPMN.

SP1-induced upregulation of lncRNA SPRY4-IT1 exerts oncogenic properties by scaffolding EZH2/LSD1/DNMT1 and sponging miR-101-3p in cholangiocarcinoma

BackgroundAccumulating evidence has indicated that long non-coding RNAs (lncRNAs) behave as a novel class of transcription products during multiple cancer processes. However, the mechanisms responsible for their alteration in cholangiocarcinoma (CCA) are not fully understood.MethodsThe expression of SPRY4-IT1 in CCA tissues and cell lines was determined by RT-qPCR, and the association between SPRY4-IT1 transcription and clinicopathologic features was analyzed. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to explore whether SP1 could bind to the promoter region of SPRY4-IT1 and activate its transcription. The biological function of SPRY4-IT1 in CCA cells was evaluated both in vitro and in vivo. ChIP, RNA binding protein immunoprecipitation (RIP) and luciferase reporter assays were performed to determine the molecular mechanism of SPRY4-IT1 in cell proliferation, apoptosis and invasion.ResultsSPRY4-IT1 was abnormally upregulated in CCA tissues and cells, and this upregulation was correlated with tumor stage and tumor node metastasis (TNM) stage in CCA patients. SPRY4-IT1 overexpression was also an unfavorable prognostic factor for patients with CCA. Additionally, SP1 could bind directly to the SPRY4-IT1 promoter region and activate its transcription. Furthermore, SPRY4-IT1 silencing caused tumor suppressive effects via reducing cell proliferation, migration and invasion; inducing cell apoptosis and reversing the epithelial-to-mesenchymal transition (EMT) process in CCA cells. Mechanistically, enhancer of zeste homolog 2 (EZH2) along with the lysine specific demethylase 1 (LSD1) or DNA methyltransferase 1 (DNMT1) were recruited by SPRY4-IT1, which functioned as a scaffold. Importantly, SPRY4-IT1 positively regulated the expression of EZH2 through sponging miR-101-3p.ConclusionsOur data illustrate how SPRY4-IT1 plays an oncogenic role in CCA and may offer a potential therapeutic target for treating CCA.

Long non-coding RNA UCA1 indicates an unfavorable prognosis and promotes tumorigenesis via regulating AKT/GSK-3β signaling pathway in cholangiocarcinoma

Long non-coding RNAs (lncRNAs) have been documented to play key roles in a wide range of pathophysiological processes, including cancer initiation and progression. Recently, the aberrant expression of urothelial carcinoma associated 1 (UCA1) was observed in many types of cancers. However, its clinical relevance and exact effects in cholangiocarcinoma (CCA) remains unknown. In the present study, we aimed to investigate the clinical significance of UCA1 and evaluate its prognostic value in patients with CCA. Besides, the functional roles of UCA1 were detected both in vitro and in vivo. Moreover, potential signaling pathways were explored to clarify the molecular mechanisms underlying CCA cell proliferation. The results indicated that UCA1 transcription is enhanced in both CCA tissue samples and cell lines, and this overexpression is associated with tumor stage (P = 0.007), lymph node invasion (P = 0.027), TNM stage (P = 0.004) and postoperative recurrence (P = 0.033) of CCA patients. Besides, UCA1 could function as an independent prognostic predictor for overall survival in patients with CCA (P = 0.014). For the part of functional assays, knockdown of UCA1 could attenuate CCA cell growth both in vitro and in vivo. Besides, UCA1 facilitates apoptosis via Bcl-2/caspase-3 pathway. In addition, UCA1 regulates migration and invasion potential of CCA cells by affecting EMT. Furthermore, AKT/GSK-3β axis was activated to upregulate CCND1 expression due to overexpression of UCA1 in CCA. To summary, UCA1 might be a potentially useful prognostic biomarker and therapeutic target for CCA.

The prognostic potential and carcinogenesis of long non-coding RNA TUG1 in human cholangiocarcinoma

Cholangiocarcinoma (CCA) is a fatal disease with increasing worldwide incidence and is characterized by poor prognosis due to its poor response to conventional chemotherapy or radiotherapy. Long non-coding RNAs (lncRNAs) play key roles in multiple human cancers, including CCA. Cancer progression related lncRNA taurine-up-regulated gene 1 (TUG1) was reported to be involved in human carcinomas. However, the impact of TUG1 in CCA is unclear. The aim of this study was to explore the expression pattern of TUG1 and evaluate its clinical significance as well as prognostic potential in CCA. In addition, the functional roles of TUG1 including cell proliferation, apoptosis, migration, invasion and epithelial-mesenchymal transition (EMT), were evaluated after TUG1 silencing. Our data demonstrated up-regulation of TUG1 in both CCA tissues and cell lines. Moreover, overexpression of TUG1 is linked to tumor size (p=0.005), TNM stage (p=0.013), postoperative recurrence (p=0.036) and overall survival (p=0.010) of CCA patients. Furthermore, down-regulation of TUG1 following RNA silencing reduced cell growth and increased apoptosis in CCA cells. Additionally, TUG1 suppression inhibited metastasis potential in vitro by reversing EMT. Overall, our results suggest that TUG1 may be a rational CCA-related prognostic factor and therapeutic target.Cholangiocarcinoma (CCA) is a fatal disease with increasing worldwide incidence and is characterized by poor prognosis due to its poor response to conventional chemotherapy or radiotherapy. Long non-coding RNAs (lncRNAs) play key roles in multiple human cancers, including CCA. Cancer progression related lncRNA taurine-up-regulated gene 1 (TUG1) was reported to be involved in human carcinomas. However, the impact of TUG1 in CCA is unclear. The aim of this study was to explore the expression pattern of TUG1 and evaluate its clinical significance as well as prognostic potential in CCA. In addition, the functional roles of TUG1 including cell proliferation, apoptosis, migration, invasion and epithelial-mesenchymal transition (EMT), were evaluated after TUG1 silencing. Our data demonstrated up-regulation of TUG1 in both CCA tissues and cell lines. Moreover, overexpression of TUG1 is linked to tumor size (p=0.005), TNM stage (p=0.013), postoperative recurrence (p=0.036) and overall survival (p=0.010) of CCA patients. Furthermore, down-regulation of TUG1 following RNA silencing reduced cell growth and increased apoptosis in CCA cells. Additionally, TUG1 suppression inhibited metastasis potential in vitro by reversing EMT. Overall, our results suggest that TUG1 may be a rational CCA-related prognostic factor and therapeutic target.

Long noncoding RNA PCAT1 regulates extrahepatic cholangiocarcinoma progression via the Wnt/β-catenin-signaling pathway

Extrahepatic cholangiocarcinoma (ECC) is a deadly disease that often responds poorly to conventional chemotherapy or radiotherapy. Long noncoding RNAs (lncRNAs) play important roles in human cancers, including ECC, and recent studies indicated that the lncRNA prostate cancer-associated transcript 1 (non-protein coding) (PCAT1) is involved in multiple cancers. However, the role of PCAT1 in ECC is unclear. Previously, we showed that PCAT1 is up-regulated in both ECC tissue samples and cell lines. Here, we showed that downregulation of PCAT1 following transfection with silencing RNA reduced ECC cell growth and increased cell apoptosis. Additionally, PCAT1 suppression inhibited ECC cell migration and invasion as determined by transwell assay. Furthermore, we determined that PCAT1 is a competing endogenous for microRNA (miR)-122, with bioinformatics analysis and luciferase-reporter assay results demonstrating that PCAT1 regulated WNT1 expression via miR-122. Moreover, PCAT1 downregulation increased levels of glycogen synthase kinase 3β and significantly decreased β-catenin levels in whole cell lysates and nuclear fractions, indicating that PCAT1 silencing inhibited the Wnt/β-catenin-signaling pathway. We also observed that exogenous expression of WNT1 reversed PCAT1-silencing-induced inhibition of ECC cell growth inhibition. These results indicated that PCAT1 silencing inhibited ECC progression by reducing Wnt/β-catenin signaling through miR-122 repression and WNT1 expression. Our findings revealed an important role of PCAT1 in ECC and suggested that PCAT1 might be a potential ECC-related therapeutic target.

ZEB1-AS1: A crucial cancer-related long non-coding RNA

Long non‐coding RNAs (lncRNAs) recently emerge as a novel class of non‐coding RNAs (ncRNAs) with larger than 200 nucleotides in length. Due to lack an obvious open reading frame, lncRNAs have no or limited protein‐coding potential. To date, accumulating evidence indicates the vital regulatory function of lncRNAs in pathological processes of human diseases, especially in carcinogenesis and development. Deregulation of lncRNAs not only alters cellular biological behavior, such as proliferation, migration and invasion, but also represents the poor clinical outcomes. Zinc finger E‐box binding homeobox 1 antisense 1 (ZEB1‐AS1), an outstanding cancer‐related lncRNA, is identified as an oncogenic regulator in diverse malignancies. Dysregulation of ZEB1‐AS1 has been demonstrated to exhibit a pivotal role in tumorigenesis and progression, suggesting its potential clinical value as a promising biomarker or therapeutic target for cancers. In this review, we make a summary on the current findings regarding the biological functions, underlying mechanisms and clinical significance of ZEB1‐AS1 in cancer progression.

Results of adjuvant radiation therapy for locoregional perihilar cholangiocarcinoma after curative intent resection

Purpose This study sought to define the role of adjuvant radiation therapy (RT) for patients with curative intent resection of perihilar cholangiocarcinoma (pCCA). Patients and methods By using the Surveillance, Epidemiology and End Results (SEER) registry, 1,917 patients with non-metastatic pCCA who underwent surgical resection from 1988 to 2009 were included in this study. Propensity score methods were used to compare the survival outcomes of patients treated with and without adjuvant RT after controlling for selection bias. Results Of the 1,917 patients, 762 (39.7%) received adjuvant RT. In the unmatched population, median overall survival (OS) for patients receiving adjuvant RT compared with those undergoing surgery alone was 23 versus 22 months (P=0.651). Patients who received adjuvant RT were younger (65 vs 68 years, P<0.001), had more regional diseases (86.0% vs 76.7%, P<0.001), and had more positive lymph nodes (43.8% vs 32.2%, P<0.001). In the matched population, adjuvant RT did not show better OS (22 vs 23 months, P=0.978) or cancer-specific survival (CSS) (17 vs 18 months, P=0.554). Conclusion Adjuvant RT is not associated with improved survival of patients with resected pCCA. These data suggest that adjuvant RT should not be routinely used to treat patients with pCCA outside research trials. Ideally, prospective randomized trials should be performed to verify the conclusion of this study.

Binding pancreaticogastrostomy anastomosis in central pancreatectomy: A single center experience

Abstract A growing number of central pancreatectomies are performed. However, reconstruction of pancreaticoenteral digestive continuity after central pancreatectomy remains debated. This study evaluates the short-term outcomes of binding pancreaticogastrostomy anastomosis in central pancreatectomy. We have reviewed our experience with 52 patients who underwent binding pancreaticogastrostomy following central pancreatectomy from February 2009 to March 2015. Indication includes 6 noninvasive intraductal papillary mucinous neoplasms, 11 neuroendocrine tumors, 12 solid pseudopapillary tumor, 9 serous cystadenoma, 6 mucinous cystadenoma, and 8 focal pancreatic traumas. The mortality rate was nil while the morbidity rate was 34.6%. Eighteen patients experienced complications including 6 pancreatic fistulas, 2 postpancreatectomy hemorrhages, 4 delayed gastric emptying, 1 hypostatic pneumonia, and 5 pancreatitis. The median postoperative length of hospital stay was 12 days (10 days for patients without fistula). None of the 52 patients were found to have pancreatic endocrine or exocrine insufficiency or recurrence of tumors. Central pancreatectomy with binding pancreaticogastrostomy is a useful and practicable surgical procedure for benign or borderline lesions of the pancreatic neck or proximal body.

Long non-coding RNA HOTAIR promotes tumorigenesis and forecasts a poor prognosis in cholangiocarcinoma

Cholangiocarcinoma (CCA) arising from the neoplastic transformation of cholangiocytes with increasing incidence in the worldwide. Unfortunately, a large amount of CCA patients lost their chance for surgery because it is hard to diagnose in the early stages. Long non-coding RNAs (lncRNAs) is closely associated with development and progression of various malignant tumors. Hox transcript antisense intergenic (HOTAIR), a negative prognostic factor for patients with gastric, liver and pancreatic carcinoma. Its transcription levels and functional roles in CCA is still unknown. Therefore, we aimed to explore the effect of HOTAIR in CCA including cell proliferation, apoptosis, migration, invasion and epithelial-to-mesenchymal transition (EMT). The results showed that HOTAIR was highly expressed both in CCA tissue samples and cell lines compared with corresponding normal bile duct tissues and Human intrahepatic biliary epithelial cells (HIBEC). Its overexpression was closely correlated with Tumor size, TNM stage and postoperative recurrence in CCA patients. Moreover, up-regulation of HOTAIR has correlation with prognosis in CCA patients. Knockdown of HOTAIR by siRNAs significantly decreased the migration and invasion but increased apoptosis of CCA cells in vitro. Overall, our study revealed that HOTAIR may play as a new potential therapeutic target and forecast poor prognosis for this fatal disease.

The role of long non-coding RNA AFAP1-AS1 in human malignant tumors

OBJECTIVES Long non-coding RNAs (lncRNAs) are a type Table of endogenous RNA longer than 200 nucleotides in length, and this kind of RNAs lack or possess limited ability of coding proteins. A large number of studies have demonstrated that lncRNAs could take part in massive biological processes, such as transcriptional activation and interference, cellular differentiation, proliferation, migration, invasion and apoptosis. The abnormal expression of lncRNAs has been clarified to play extremely important roles in various diseases, especially in human cancers. LncRNA actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) is a newly recognized cancer-related lncRNA deriving from the antisense strand of DNA at the AFAP1 coding gene locus. A slew of new studies suggest that AFAP1-AS1 is involved in many kinds of malignant tumors. Moreover, in recent years, the dysregulated expression of AFAP1-AS1 has been confirmed to be associated with oncogenesis and tumor progression. Evidence has increasingly shown that AFAP1-AS1 could probably serve as a novel potential molecular biomarker in tumor diagnosis and therapeutic target in tumor treatment. In this review, we sum up present stage new hottest research issues in respect of the biological functions and molecular mechanisms of AFAP1-AS1 in occurrence and progression of human tumors. MATERIALS AND METHODS In this review, we summarize the recent researches about the expression and molecular biological mechanisms of lncRNA AFAP1-AS1 in tumor development. Existing relevant studies are acquired and analyzed by searching Pubmed, BioMedNet, GEO database and Academic Search Elit systematically. RESULTS Long non-coding RNA AFAP1-AS1 is an important tumor-associated lncRNA and its aberrant expression has been found in many malignancies so far, including pancreatic ductal adenocarcinoma, cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, esophageal cancer, nasopharyngeal carcinoma, lung cancer, ovarian cancer, breast cancer, retinoblastoma, laryngeal cancer, tongue squamous cell carcinoma and thyroid cancer. In addition, the dysregulated expression of AFAP1-AS1 is related to carcinogensis, overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and tumor progression containing lymph node metastasis, distant metastasis, histological grade, tumor size and tumor stage. CONCLUSIONS A series of studies provide detailed information to understand lncRNA AFAP1-AS1 role in various human cancers. LncRNA AFAP1-AS1 is an oncogene in tumors that have been studied so far, and it may act as a useful tumor biomarker and therapeutic target.