Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway

Abstract

Background: Accumulation evidence indicates the vital role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including pancreatic cancer (PC). However, the role and the molecular mechanism of long non-coding RNA 00976 is unclear in pancreatic cancer. Methods: In situ hybridization (ISH) and qRT-PCR was performed to investigate the association between linc00976 expression and the clinicopathological characteristics and prognosis of patients with PC. Subsequently, linc00976 over-expression vector and shRNAs were transfected into PC cells to up-regulate or down-regulate linc00976 expression. Loss-and gain-of function assays were performed to investigate the role of linc00976 in proliferation and metastasis in vitro and vivo. ITRAQ, bioinformatic analysis and rescue assay were used to illustrate the ceRNA mechanism network of linc00976/miR-137/OTUD7B and its downstream EGFR/MAPK signaling pathway. Results: linc00976 expression was overexpressed in PC tissues and cell lines and was positively associated with poorer survival in patients with PC. Function studies revealed that linc00976 knockdown significantly suppressed cell proliferation, migration and invasion in vivo and in vitro, whereas its overexpression reversed these effects. Based on Itraq results and online database prediction, Ovarian tumor proteases OTUD7B was found as a downstream gene of linc00976, which deubiquitinated EGFR mediates MAPK signaling activation. Furthermore, Bioinformatics analysis and luciferase assays and rescue experiments revealed that linc00976/miR137/OTUD7B established the ceRNA network modulating PC cell proliferation and tumor growth. Conclusion: The present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway, suggesting that linc00976/miR-137/OTUD7B/EGFR axis may act as a potential biomarker and therapeutic target for PC.

LncRNA PSMB8-AS1 contributes to pancreatic cancer progression via modulating miR-382-3p/STAT1/PD-L1 axis

“…As previously reported, lncRNAs could complete with the binding of miRNA to promote the target gene expression in transcription and translation [ 22 – 24 ]. Also, lncRNA/miRNA and the target gene-mediated ceRNA regulation network has been shown in PC progress [ 16 , 18 ]. Our functional assay demonstrated that PSMB8-AS1 could act as the upstream gene of miRNA-382–3p.…”

“…It is well known that the competing endogenous RNA (ceRNA) regulation network is the most frequently reported molecular mechanism to elucidate the function in tumor biology progress [16][17][18][19]. Therefore, miRNA as the pivotal downstream of lncRNA mediated tumorigenesis via regulation of the target gene.…”

Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms

“…Stimuli such as oxidative stress can make phosphatidylserine appear outside on the pancreatic cancer cell membrane, finally leading to dysregulation of factors and cells such as VEGF and macrophages, making prognosis of patients unfavorable [ 66 – 68 ]. The EGFR pathway contributes to pancreatic cancer growth and accelerates invasion of the cancer as a result of lnc00976 overexpression, which can deteriorate the outcome of patients [ 69 , 70 ].…”

Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms

“…Stimulations such as oxidative stress can make phosphatidylserine appear outside on the pancreatic cancer cell membrane, nally leading to dysregulation of factors and cells like VEGF and macrophages, making prognosis of patients unfavorable (66)(67)(68). The EGFR pathway contributes to pancreatic cancer growth and accelerates invasion of the cancer as a result of linc00976 overexpression, which can deteriorate outcome of patients (69,70).…”