Xue-Liang Fu

Analysis of long non-coding RNA expression profiles in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients’ clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC.

High expression of DDR1 is associated with the poor prognosis in Chinese patients with pancreatic ductal adenocarcinoma

BackgroundDiscoidin domain receptors 1 (DDR1), a subtype of DDRs, has been reported as a critical modulator of cellular morphogenesis, differentiation, migration and invasion.Methods and resultsIn this study, we investigated the expression of DDR1 and its clinical association in Chinese patients with pancreatic ductal adenocarcinoma (PDAC). Across a cohort of 30 patients, we examined DDR1 expression in paired PDAC and corresponding adjacent non-tumor tissues by real-time quantitative PCR (RT-qPCR), or western blotting. DDR1 expression is significantly higher in PDAC, as compared to normal adjacent tissue, confirming results from the Oncomine databases. We validated DDR1 expression by immunohistochemistry across a non-overlapping cohort of 205 PDAC specimens. Kaplan-Meier survival curves indicate that increased expression of DDR1 is associated with a poor prognosis in PDAC patients (P = 0.013). Multivariate Cox regression analysis identified DDR1 expression, age, N classification and liver metastasis as independent prognostic factors in PDAC.ConclusionsThis study demonstrated that DDR1 can well serve as a novel prognostic biomarker in PDAC.

Clinicopathological, treatment, and prognosis study of 43 gastric neuroendocrine carcinomas

AIM To provide more information and therapeutic methods about gastric neuroendocrine carcinomas (G-NECs) which occur rarely but are highly malignant and clinically challenging. METHODS We retrospectively analyzed the clinicopathological characteristics, treatments, and prognosis of 43 G-NEC patients at our hospital between January 2007 and December 2014. The diagnosis was based on the 2010 World Health Organization criteria. RESULTS Forty-three G-NECs containing 39 small cell carcinomas and 4 large cell NECs with Ki67 > 60% were included in this study, accounting for only 0.95% of all gastric carcinomas. The median patient age was 62 years (range, 33-82) and the male-to-female ratio was 4.4:1. All patients underwent surgery, including 38 curative resections and 5 palliative resections. Among these 43 patients, nearly half (48.84%) of these tumors were located in the cardiac region of the stomach, regional lymph node metastasis was found in 31 cases (72.09%), and liver metastasis was found in 6 cases (13.95%). Follow-up information was got for 40 patients. Twenty-three die of this disease with a median survival of 31 mo (range 1-90). The 1-year, 2-year, 3-year, and 5-year survival rate was 77.50%, 57.04%, 44.51%, and 35.05%, respectively. Survival was better in patients with tumor located in the cardiac region of the stomach, less than 7 lymph nodes metastasis and no liver metastasis. Five patients did not undergo postoperative chemotherapy, and the median survival time for these patients was 15 mo. For the remaining 34 patients who received postoperative chemotherapy, the median survival time was 44 mo and those received etoposide, cisplatin, and Paclitaxel survived the best. One patient with resected liver metastasis who received postoperative Capecitabine plus Oxaliplatin and Paclitaxel systemic chemotherapy plus octreotide LAR (30 mg intramuscularly, every 4 wk, for 2 years) has survived for 74 mo with no recurrence. CONCLUSION G-NECs are mostly nonfunctioning, which lead to a delay in detection. Local and/or distant metastases were noticed in most patients when diagnosed, and they required postoperative medical treatment. Adjuvant etoposide, cisplatin plus Paclitaxel systemic chemotherapy is recommended for these patients.

Downregulation of RPL15 may predict poor survival and associate with tumor progression in pancreatic ductal adenocarcinoma

Early diagnosis and treatment in pancreatic ductal adenocarcinoma (PDAC) is still a challenge worldwide. The poor survival of PDAC patients mainly due to early metastasis when first diagnosed and lack of prognostic biomarker. Ribosomal protein L15 (RPL15), an RNA-binding protein, is a component of ribosomal 60S subunit. It was reported that RPL15 is dysregulated in various type of cancers. However, little is known about the role of RPL15 in PDAC carcinogenesis and progression. Herein, we clarified RPL15 expression status may serve as an independent prognostic biomarker in three independent PDAC patient cohorts. We found that RPL15 was dramatically decreased in PDAC tissues and cell lines. The high expression of RPL15 was inversely correlated with TNM stage, histological differentiation, T classification and vascular invasion. Low expression of RPL15 was significantly associated with poor overall survival of PDAC patients. Furthermore, we demonstrated that the reduction of RPL15 may promote invasion ability of pancreatic cell by inducing EMT process. In conclusion, decreased RPL15 expression is associated with invasiveness of PDAC cells, and RPL15 expression status may serve as a reliable prognostic biomarker in PDAC patients.

Overexpressed EDIL3 predicts poor prognosis and promotes anchorage-independent tumor growth in human pancreatic cancer.

Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein associated with vascular morphogenesis and remodeling, is commonly upregulated in multiple types of human cancers and correlates with tumor progression. However, its expression pattern and underlying cellular functions in pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. In current study, we observed that expression of EDIL3 was significantly up-regulated in PDAC compared with normal controls in both cell lines and clinical specimens. In addition, elevated EDIL3 expression was positively correlated with patients’ TNM stage and T classification. Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients. Multivariate Cox regression analysis confirmed EDIL3 expression, age, lymph node metastasis and histological differentiation as independent prognostic factors in PDAC. Knockdown of EDIL3 showed no significant influence on cell viability, migration, invasion and starvation-induced apoptosis, but compromised anoikis resistance and anchorage independent tumor growth of PDAC cells. Meanwhile, treatment with recombinant EDIL3 protein markedly promoted anoikis resistance and anchorage independent tumor growth. Mechanistically, we demonstrated that altered protein expression of Bcl-2 family might contribute to the oncogenic activities of EDIL3. In conclusion, this study provides evidences that EDIL3 is a potential predictor and plays an important role in anchorage independent tumor growth of PDAC and EDIL3-related pathways might represent a novel therapeutic strategy for treatment of pancreatic cancer.

High Expression of FAM83B Predicts Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma and Correlates with Cell Cycle and Cell Proliferation

FAM83B (family with sequence similarity 83, member B) seems to emerge as a new class of players involved in the development of a variety of malignant tumors. Yet the molecular mechanisms are not well understood. The present study is intended to investigate the expression and function of FAM83B in pancreatic ductal adenocarcinoma (PDAC). In this study, we found that the expression of FAM83B was significantly increased both in PDAC cell lines and PDAC tumor tissues. FAM83B expression was positively related with advanced clinical stage and poor vital status. Higher FAM83B expression predicted shorter overall survival in PDAC patients, regardless of lymphatic metastasis status and histological differentiation. Actually, FAM83B may act as an independent prognostic indicator as well. Whats more, down-regulation of FAM83B in PDAC cells contributed to G0/G1 phase arrest and inhibition of cell proliferation. Finally, a subcutaneous xenograft model indicated that knockdown of FAM83B significantly reduced the tumor volume in vivo. Our findings have provided supporting evidence for the potential molecular biomarker role of FAM83B in PDAC. Its of great interest and broad significance to target FAM83B in PDAC, which may conduce to develop a meaningful and effective strategy in the diagnosis and treatment of PDAC.

Efficacy of Neo-Adjuvant Chemoradiotherapy for Resectable Pancreatic Adenocarcinoma: A PRISMA-Compliant Meta-Analysis and Systematic Review.

AbstractWe have conducted a meta-analysis and systematic review to determine the overall survival, mortality rate, and complete resection rate of neo-adjuvant chemoradiotherapy (CRT) compared with pancreaticoduodenectomy alone in patients with pancreatic adenocarcinoma. Whether neo-adjuvant CRT is beneficial in the treatment of resectable pancreatic cancer or not, it is still a controversial issue.Medline and Cochrane were searched with relevant terms. Eight studies with a total of 833 participants were selected. The meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.The analysis revealed neo-adjuvant group may have a benefit in the overall survival, as compared with the resection group, although it did not reach statistical significance (pooled hazard ratio = 0.87, 95% confidence interval [CI] = 0.75–1.00, P = 0.051). We found no difference in the in-hospital mortality rate (pooled odds ratio [OR] = 1.27, 95% CI = 0.35–4.58, P = 0.710). The complete resection rate was significantly higher in the neo-adjuvant group than in the resection group (pooled OR = 2.39, 95% CI = 1.21–4.74, P = 0.012).This meta-analysis found that there was no significant difference in the overall survival between patients treated with neo-adjuvant CRT or pancreaticduodenectomy.

Decreased expression of USP9X is associated with poor prognosis in Chinese pancreatic ductal adenocarcinoma patients

The present study aimed to investigate the expression level of ubiquitin specific peptidase 9X (USP9X) and its clinical significance in Chinese patients with pancreatic ductal adenocarcinoma (PDAC). The mRNA expression levels of USP9X in 30 paired PDAC tissue samples were examined by reverse transcription-quantitative polymerase chain reaction. The protein expression of USP9X was analyzed by immunohistochemistry (IHC) in a tissue microarray containing 205 PDAC specimens. All analyses were performed by SPSS 20.0 and GraphPad Prism 5.0 software. The USP9X mRNA level was significantly decreased in 18/30 (60.0%) PDAC tissue samples compared with matched surrounding non-tumor tissue samples. The results of IHC revealed that decreased expression of USP9X was inversely associated with liver metastasis (P=0.032). Kaplan-Meier survival curves indicated that patients with high expression of USP9X presented a longer clinical overall survival time (P<0.001). Univariate and multivariate COX regression analysis revealed that USP9X protein expression level was a significant, and independent prognostic factor for the overall survival rate of patients with PDAC. The results of the present study indicate that USP9X may serve as a candidate tumor suppressor and prognostic biomarker in PDAC.

The role of Dickkopf-1 as a potential prognostic marker in pancreatic ductal adenocarcinoma

ABSTRACT Dickkopf-1(DKK-1), the downstream target of β-catenin/T-cell factor, participates in a negative feedback loop in the Wnt signaling and reported as an important biomarker in many tumors. In this study, we analyzed the expression of DKK-1 in pancreatic ductal adenocarcinoma (PDAC) patients at both mRNA and protein levels. We used real-time PCR to detect the expression of DKK-1 in 32 PDAC and paired adjacent non-tumor tissues, results suggested that the expression of DKK-1 was increased in PDAC tissues. We found the similar results in the analysis of 3 independent microarray data sets. Immunohistochemical staining of 311 pairs of PDAC tissues suggested that DKK-1 expression was significantly associated with T classification (P = 0.039) and lymph node metastasis (P = 0.035). Furthermore, Kaplan-Meier analysis for DKK-1 expression demonstrated that patients with higher DKK-1 level had shorter overall survival (OS) and relapse-free survival (RFS) time in Ren Ji cohort and online PDAC database at both mRNA and protein levels. Univariable and multivariable Cox regression analysis confirmed that DKK-1 as well as lymph node metastasis and histology were independent predictors of OS in patients with PDAC. This study demonstrated that DKK-1 may be a predictor for prognosis in PDAC patients.