The serum miR‐21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR‐21 expression confers chemoresistance by targeting FasL

Abstract

miR-21 expression in cancer tissue has been reported to be associated with the clinical outcome and activity of gemcitabine in pancreatic cancer. However, resection is possible in only a minority of patients due to the advanced stages often present at the time of diagnosis, and safely obtaining sufficient quantities of pancreatic tumor tissue for molecular analysis is difficult at the unresectable stages. In this study, we investigated whether the serum level of miR-21 could be used as a predictor of chemosensitivity. We tested the levels of serum miR-21 in a cohort of 177 cases of advanced pancreatic cancer who received gemcitabine-based palliative chemotherapy. We found that a high level of miR-21 in the serum was significantly correlated with a shortened time-to-progression (TTP) and a lower overall survival (OS). The serum miR-21 level was an independent prognostic factor for both the TTP and the OS (HR 1.920; 95% CI, 1.274-2.903, p = 0.002 for TTP and HR 1.705; 95% CI, 1.147-2.535, p = 0.008 for OS). The results from a functional study showed that gemcitabine exposure down-regulated miR-21 expression and up-regulated FasL expression. The increased FasL expression following gemcitabine treatment induced cancer cell apoptosis, whereas the ectopic expression of miR-21 partially protected the cancer cells from gemcitabine-induced apoptosis. Additionally, we confirmed that FasL was a direct target of miR-21. Therefore, the serum level of miR-21 may serve as a predictor of chemosensitivity in advanced pancreatic cancer. Additionally, we identified a new mechanism of chemoresistance mediated by the effects of miR-21 on the FasL/Fas pathway.

MiR-21 Upregulation Induced by Promoter Zone Histone Acetylation is Associated with Chemoresistance to Gemcitabine and Enhanced Malignancy of Pancreatic Cancer Cells

“…In addition, cancer tissue miR-21 has been shown to be a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer (Hwang et al, 2010). Further study showed that the serum level of miR-21 can be used as a predictor of chemosensitivity in advanced PDAC (Wang et al, 2013a). We also found that gemcitabine-resistant advanced PDAC patients had higher serum miR-21 level compared with gemcitabine-sensitive subjects.…”

“…Recent studies have shown that miRNAs are stably detectable in plasma or serum, and a strong correlation exists between tumor-derived circulating miRNAs and miRNAs directly within tumor cells (Chen et al, 2008;Mitchell et al, 2008). The serum level of miR-21 could serve as a surrogate for the expression level of miR-21 in the tumor tissue and be used as a predictor of the chemosensitivity of advanced PDAC treated with gemcitabine (Wang et al, 2013a). In our study, serum miR-21 levels were significantly higher in gemcitabine-resistant PDAC patients compared with gemcitabine-sensitive subjects.…”

Identification of Serum MicroRNA-21 as a Biomarker for Early Detection and Prognosis in Human Epithelial Ovarian Cancer

“…Zhang et al (2011b) confirmed elevated serum miR-21 levels in patients with hormone-refractory prostate cancer and its potential value in predicting the efficacy of docetaxelbased chemotherapy. Wang et al (2012) tested the levels of serum miR-21 in advanced pancreatic cancer patients who received gemcitabine-based palliative chemotherapy, and the results showed serum miR-21 level was an independent prognostic factor for both the time-to-progression (TTP) and the OS. So, miR-21 may play an important role not only in tumor initiation but also in development and drug resistance, and serum miR-21 would offer great hope for the diagnosis and prognosis of many human malignancies..…”

Major apoptotic mechanisms and genes involved in apoptosis

“…Therefore, miR-221 and miR-222 are oncogenic miRNAs that induce drug resistance and block apoptosis in several cancer types such as gliomas [164]. Another oncogenic miRNA exerting its anti-apoptotic effects by inhibiting FasL directly is miR-21, which is found to be upregulated in advanced pancreatic cancer patients [165]. miR-24 regulates apoptosis by binding to coding sequence of Fas-associated factor 1 (FAF1) mRNA and induced apoptosis of several different types of cancer [166].…”