Expression Levels of microRNAs miR-93 and miR-200a in Pancreatic Adenocarcinoma with Special Reference to Differentiation and Relapse-Free Survival

Abstract

Objectives: Protein levels of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) have been proposed as prognostic factors in pancreatic ductal adenocarcinomas (PDACs). These cellular redox-state-regulating enzymes are targeted by several microRNAs, including miR-93 and miR-200a. Methods: We assessed mRNA levels of Nrf2 and Keap1 and tissue expression of miR-93 and miR-200a in 51 patients with surgically treated PDAC. Expression levels were separately measured in malignant cells and adjacent benign cells. Results: Keap1 and Nrf2 mRNA expression levels in cancer cells were lower than in adjacent benign tissue (Wilcoxon’s test; p = 0.0015 and p = 0.000032, respectively). Conversely, miR-93 expression was higher in cancer cells than in adjacent benign tissue (p = 0.00082). Low levels of miR-93 and miR-200a in cancer cells were associated with poorer differentiation (p = 0.004 and p = 0.002, respectively). In univariate survival analysis, benign-tissue levels of miR-200a above the median predicted better relapse-free survival (RFS) (p = 0.045). Conclusions: High miR-93 and miR-200a levels in cancer cells of PDAC were associated with better differentiation, and miR-200a expression in benign tissue with excellent RFS. Keap1 and Nrf2 mRNA levels showed prominent down-regulation in cancerous versus benign tissue, but they were not associated with disease aggressiveness or outcome.

Differential Expression of MicroRNAs in Silent and Functioning Corticotroph Tumors

“…Thus, we found that miR-488 and miR-200a expression levels were positively correlated with tumor size, suggesting that these miRNAs could participate in the growth of these tumors. Our results are concordant with other studies reporting that miR-488 and miR200 play a role as tumor suppressor agents in several types of cancers [ 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. In addition, we observed a strong negative correlation between the expression of MAP3K8 and miR-488, miR-200a and miR-103, and also between the expression of MEK and miR-488 and miR-103 in silent CTs.…”

Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression

“…In esophageal squamous cell carcinoma, methylseleninic acid activated KEAP1/NRF2 pathway via upregulating miR-200a , the latter inhibited KEAP1 expression and induced expression of NRF2 96 . In breast cancer and pancreatic adenocarcinoma, miR-200a suppression reverted expression of KEAP1 and then inhibited NRF2 and promoted the anchorage-independent cell growth in vitro 97 . In turn, NRF2 enhances miRNAs expression via binding to the antioxidative response element box.…”

Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review

“…Mechanistically, aPKCι and PALB2 share with Nrf2 a highly conserved Keap1-binding motif and compete with Nrf2 for Keap1 binding, protecting Nrf2 from Keap1-mediated protein degradation [41, 42]. Moreover, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have also been found to regulate the expression of Keap1 in PC [43, 52]. A lncRNA, KRAL (Keap1 regulation-associated lncRNA) directly interacts with miR-141as a competing endogenous RNA (ceRNA) and increases the expression of Keap1, leading to the inactivation of Nrf2 and the enhancement of chemosensitization to cancer cells [43].…”

“…Decreased deoxycytidine kinase (dCK) has been shown to inhibit PC cell growth and metastasis and sensitize PC cells to gemcitabine treatment by down-regulating the Nrf2 transcriptional activity and decreasing the expression of ARE-driven antioxidant genes [50]. LncRNAs and miRNAs are also involved in the regulation of Nrf2 expression in PC [52]. A lncRNA, termed NRAL (Nrf2 regulation-associated lncRNA) directly binds to miR-340-5p and inhibits the miR-340-5p-mediated repressing activity of the Nrf2–3’UTR, therefore increasing the expression of Nrf2 and inducing drug resistance in PC cells [51].…”