MicroRNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer

Abstract

Background:Pancreatic cancer has a poor prognosis because of its high refractoriness to chemotherapy and tumour recurrence, and these properties have been attributed to cancer stem cells (CSCs). MicroRNA (miRNA) regulates various molecular mechanisms of cancer progression associated with CSCs. This study aimed to identify the candidate miRNA and to characterise the clinical significance.Methods:We established gemcitabine-resistant Panc1 cells, and induced CSC-like properties through sphere formation. Candidate miRNAs were selected through microarray analysis. The overexpression and knockdown experiments were performed by evaluating the in vitro cell growth and in vivo tumourigenicity. The expression was studied in 24 pancreatic cancer samples after laser captured microdissection and by immunohistochemical staining.Results:The in vitro drug sensitivity of pancreatic cancer cells was altered according to the miR-1246 expression via CCNG2. In vivo, we found that miR-1246 could increase tumour-initiating potential and induced drug resistance. A high expression level of miR-1246 was correlated with a worse prognosis and CCNG2 expression was significantly lower in those patients.Conclusions:miR-1246 expression was associated with chemoresistance and CSC-like properties via CCNG2, and could predict worse prognosis in pancreatic cancer patients.

Cyclin G2: A novel independent prognostic marker in pancreatic cancer

“…In gastric cancer, CCNG2 expression correlates with the extent of differentiation: CCNG2 expression is high in well-differentiated adenocarcinomas and low in poorly-differentiated adenocarcinomas (12). In our previous study, CCNG2 induced apoptosis and was partially associated with cancer stemness in a pancreatic cancer cell line (13). In summary, CCNG2 is heavily involved in cancer progression, including proliferation, invasion, chemoresistance and differentiation in various cancer types.…”

“…Previous studies have reported that CCNG2 is involved in a variety of functions associated with cancer progression, including the regulation of cell proliferation (8-10), chemoresistance (8), DNA repair (11) and cell differentiation (12). Furthermore, our previous study demonstrated that CCNG2 was associated with chemoresistance and cancer stemness via cell apoptosis in pancreatic cancer (13). Recently, CCNG2 has been reported as a novel prognostic marker in several types of cancer (14)(15)(16)(17).…”

“…Cyclins positively regulate cell proliferation to a large extent. However, unexpectedly, CCNG2 has been reported to regulate cell proliferation as a tumor suppressor gene and its decreased expression is associated with malignant phenotypes in several types of cancer (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Previous studies have reported that CCNG2 is involved in a variety of functions associated with cancer progression, including the regulation of cell proliferation (8-10), chemoresistance (8), DNA repair (11) and cell differentiation (12).…”

Chemoresistance in pancreatic cancer: Emerging concepts

“…miRs regulate the gene expression in the majority of biological processes in the cell, and therefore have been hypothesized to serve an important role in the chemoresistance to standard treatment regimens in pancreatic cancer. Numerous studies demonstrated that miRs are differentially expressed in a variety of types of cancer (44)(45)(46)(47)(48)(49)(50). A study examining the miR profile of gemcitabine-sensitive and resistant pancreatic cancer cell lines reported the presence of 33 differentially regulated miRs (44).…”

“…Another study demonstrated that miR-21 overexpression results in an increased sensitivity to gemcitabine via a decrease in the expression levels of the p85α subunit of phosphatidylinositol-4,5-biphostphate 3-kinase (47). miR-1246 has been revealed to increase stemness and induce drug resistance in pancreatic cancer cell lines (48). Similarly, miR-221/222 was demonstrated to induce pancreatic cancer progression through the regulation of MMPs (49), indicating that miRs may be pro-and anti-oncogenic.…”