microRNA-374a suppresses colon cancer progression by directly reducing CCND1 to inactivate the PI3K/AKT pathway

Abstract

microRNA-374a (miR-374a) exhibits oncogenic functions in various tumor types. Here we report that miR-374a suppresses proliferation, invasion, migration and intrahepatic metastasis in colon adenocarcinoma cell lines HCT116 and SW620. Notably, we detected that PI3K/AKT signaling and its downstream cell cycle factors including c-Myc, cyclin D1 (CCND1), CDK4 and epithelial-mesenchymal transition (EMT)-related genes including ZEB1, N-cadherin, Vimentin, Slug, and Snail were all significantly downregulated after miR-374a overexpression. Conversely, cell cycle inhibitors p21 and p27 were upregulated. Expression of E-cadherin was only decreased in HCT116, without any obvious differences observed in SW620 cells. Furthermore, luciferase reporter assays confirmed that miR-374a could directly reduce CCND1. Interestingly, when CCND1 was silenced or overexpressed, levels of pPI3K, pAkt as well as cell cycle and EMT genes were respectively downregulated or upregulated. We examined miR-374a levels by in situ hybridization and its correlation with CCND1 expression in CRC tumor tissues. High miR-374a expression with low level of CCND1 was protective factor in CRC. Together these findings indicate that miR-374a inactivates the PI3K/AKT axis by inhibiting CCND1, suppressing of colon cancer progression.

MicroRNA-374 Exerts Protective Effects by Inhibiting SP1 Through Activating the PI3K/Akt Pathway in Rat Models of Myocardial Ischemia-Reperfusion After Sevoflurane Preconditioning

“…In a recent study, through directly binding the 3' untranslated regions of the tumor-suppressor genes PTEN and CDKN1A , miR-93 inhibited their expression and activated the c-Met/PI3K/Akt pathway by regulating c-Met protein expression [22]. Furthermore, Chen et al found that after overexpression of miR-374a, the PI3K/Akt signaling pathway and its downstream cell cycle factors, including c-myc, CDK4, CCND1 and EMT-related genes such as ZEB1, Snail, Vimentin and N-cadherin, were downregulated [12]. …”

“…Lately, it was shown that miRs could be potential therapeutic targets for alleviating I/R injury through altering key signaling elements [11]. It has been demonstrated that by suppressing CCND1, miR-374a could inactivate the PI3K/AKT axis, inducing the inhibition of colon cancer progression [12]. As an important part of the protective mechanism of ischemic preconditioning, the phosphoinositide 3-kinase (PI3K)/Akt pathway plays a major role in controlling cell growth, survival, proliferation and migration, with an improving function in I/R through activating Akt [13].…”

A six‐microRNA signature to predict outcomes of patients with gastric cancer

“…On the contrary, another study showed that miRNA-100 could promote apoptosis of GC cell through Notch-apoptosis pathway and improve the sensitivity of GC cells to chemotherapy [29]. miRNA-374a could promote proliferation, migration, and invasion of GC cells through downregulating SRCIN1 while inhibit proliferation, invasion, migration, and intrahepatic metastasis of colon cancer cells by targeting CCND1 [30,31]. In our study, miRNA-100 was a risk microRNA and miRNA-374a was a protective microRNA.…”

Total ginsenosides of Chinese ginseng induces cell cycle arrest and apoptosis in colorectal carcinoma HT‑29 cells

“…Cyclin D1 and c-Myc are the downstream targets of Wnt/β-catenin signaling pathway, the inhibition of which causes suppression of tumor growth, epithelial mesenchymal transition (EMT), and cell motility of CRC (36). Besides, c-Myc, Cyclin D1, Cdk2, and Cdk4 are also the downstream cell cycle factors of PI3K/Akt signaling pathway in CRC, while p21 and p27 are its downstream cell cycle inhibitors (37,38). Furthermore, c-Myc and Cyclin D1 are cell proliferative effectors in the downstream of NF-κB signaling pathway in CRC (39).…”