MicroRNA-221 and MicroRNA-222 in Common Human Cancers

Expression, Function, and Triggering of Tumor Progression as a Key Modulator

Sima Amini, MSc; Atefe Abak, MSc; Ebrahim Sakhinia, PhD; Alireza Abhari, PhD

Disclosures

Lab Med. 2019;50(4):333-347. 

In This Article

Regulation of Drug Resistance by MiR-221/-222

Recent study reports[68–70] have shown that miRNAs can regulate drug resistance in cancer through acting on multiple signaling pathways. With the detection of the role of miRNAs in drug resistance, another promising approach has emerged: the use of miRNAs encoded by the human genome as diagnostic tools to predict drug response. Thus, knowledge of all the miRNAs associated with drug resistance will be key to designing drugs with greater efficacy and safety, which will have positive health and economic ramifications.

Also, Jiang et al[36] reported that PUMA is directly targeted by miR-222 in oral squamous-cell carcinoma (OSCC). Their findings demonstrated that knockdown of miR-222 by AS-miR-222 elevated PUMA expression and caused an increase in cisplatin sensitization in UM1 cells. The authors also indicated that AS-miR-222 and cisplatin suppress proliferation and promote apoptosis in OSCC.

Regarding the fact that PI3K/AKT is an active oncogenic pathway during malignancy in liver cells, Liu et al[27] report that miR-222 enhances sorafenib resistance in HCC through the PI3K/AKT pathway. Also, Garofalo et al[31] detected that miR-221/-222 induces TRAIL resistance through PTEN and TIMP metallopeptidase inhibitor 3 (TIMP3), as targets, in NSCLC and malignant hepatoma cells. They showed that miR-221/-222 can regulate TRAIL sensitivity in NSCLC through interaction with P27 and TRAIL-induced caspase machinery.

In another study, Rao et al[50] reported that miR-221/-222 can enhance fulvestrant resistance in breast cancer by regulating multiple oncogenic pathways, such as Wnt and transforming growth factor β (TGF-β) signaling processes. Also, they observed that miR-221/-222 can increase the expression of β-catenin, frizzled class receptor 5 (FZD5), and SMADs. Overexpression of β-catenin culminated in fulvestrant resistance in MCF7 cells. Thus, β-catenin is the main regulator of the WNT signaling cascade, and SMADs are the key regulators of the TGF-β signaling pathway.

VEGFR2 and C-KIT are 2 targets of miR-221/-222, and both of them are sunitinib receptors. Also, Khella et al[71] reported that upregulation of these 2 miRNAs associates with sunitinib resistance in renal-cell carcinoma (RCC). This occurred because of a decline in these 2 targeted proteins, so they are not available to join with sunitinib. Also, Acunzo et al[72] reported that upregulation of miR-130a could suppress miR-221/-222 by targeting MET. MiR-130a could sensitize NSCLC cells to TRAIL by decreasing miR-221/-222.

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