miR-211 Modulates Gemcitabine Activity Through Downregulation of Ribonucleotide Reductase and Inhibits the Invasive Behavior of Pancreatic Cancer Cells

Abstract

Only a subset of radically-resected pancreatic ductal adenocarcinoma (PDAC) patients benefit from gemcitabine-based chemotherapy, thus the identification of novel prognostic factors is essential. In a high-throughput, microRNA (miRNA) array, miR-211 emerged as the best discriminating miRNA, with high expression associated with long survival. Here, we further explored the biological role of miRNA-211 in gemcitabine activity in the human PDAC cells (SUIT-2) subclones SUIT2-007 and SUIT2-028. Our results showed that miR-211 was expressed differentially in PDAC cells characterized by differential metastatic capability. In particular, S2-028 with lower metastatic ability had a higher expression of miR-211, compared to the S2-007 with higher metastatic capacity. Enforced expression of miR-211 via pre-miR-211 significantly reduced cell migration and invasion (e.g., 40% reduction of invasion of SUIT2 cells, compared to control; p<.05). Moreover, we demonstrated that induction of the miR-211 expression in the cells increased the sensitivity to gemcitabine and reduced the expression of its target ribonucleotide reductase subunit 2 (RRM2). In conclusion, miR-211 functional analyses suggested the role of RRM2 as a target of miR-211 in the modulation of gemcitabine sensitivity. Moreover, inhibition of cell migration and invasion might explain the less aggressive behavior of pancreatic cancer cells with higher expression levels of miR-211.

MicroRNA 211 expression is upregulated and associated with poor prognosis in colorectal cancer: a case–control study

“…Several studies have investigated the effect of miR-211 expression on tumorigenesis [10][11][12][13][14][15][16][17][18][19]. Our results are in line with previous findings showing that miR-211 may function as an oncogene [10][11][12].…”

“…Moreover, Chu et al [12] indicated that miR-211 could facilitate head and neck squamous cell carcinoma (HNSCC) progression via the inhibition of transforming growth factor-β type II receptor (TGFβRII), disrupted Smad3 phosphorylation, and upregulated c-Myc expression. In contrast with these studies, some authors have reported opposite findings [13][14][15][16][17][18][19]. For example, previous researches were reported that in melanoma cells, overexpression of miR-211 could act as a tumor suppressor miRNA by inhibiting metastasis and invasion through regulation of oncogenes [13][14][15][16][17].…”

“…For example, previous researches were reported that in melanoma cells, overexpression of miR-211 could act as a tumor suppressor miRNA by inhibiting metastasis and invasion through regulation of oncogenes [13][14][15][16][17]. Besides, Giovannetti et al [18] and Maftouh et al [19] demonstrated that low miR-211 expression was an independent factor of poor prognosis of pancreatic ductal adenocarcinoma. Based on these data, it is possible that the significant difference in the results of studies may be due to different roles of miR-211 during tumorigenesis.…”

“…Several studies suggested that overexpression of miR-211 may function as an oncogene in some cancers including oral carcinoma, colorectal carcinoma, and head and neck carcinoma [10][11][12]. However, previous researches reported that in melanoma and pancreatic cancer, overexpression of miR-211 could act as a tumor suppressor miRNA by inhibiting metastasis, invasion, and poor prognosis through regulation of oncogenes [13][14][15][16][17][18][19]. Based on these data, role of miR-211 during tumorigenesis is still contentious and may exhibit cell-specific regulatory manner but the detailed mechanisms underlying its pro/anti-oncogenic effects remain to be addressed.…”

miR-211 promotes non-small cell lung cancer proliferation by targeting SRCIN1

“…Trpm1 is a target gene of microphthalmia-associated transcription factor (MITF) [31,[36][37][38]. It has also been demonstrated that miR-211 can impact cell invasion, proliferation, and migration in many cancers [28][29][30].…”