miR-221/222 as biomarkers and targets for therapeutic intervention on cancer and other diseases: A systematic review

Abstract

Among deregulated microRNAs (miRs) in human malignancies, miR-221 has been widely investigated for its oncogenic role and as a promising biomarker. Moreover, recent evidence suggests miR-221 as a fine-tuner of chronic liver injury and inflammation-related events. Available information also supports the potential of miR-221 silencing as promising therapeutic intervention. In this systematic review, we selected papers from the principal databases (PubMed, MedLine, Medscape, ASCO, ESMO) between January 2012 and December 2020, using the keywords "miR-221" and the specific keywords related to the most important hematologic and solid malignancies, and some non-malignant diseases, to define and characterize deregulated miR-221 as a valuable therapeutic target in the modern vision of molecular medicine. We found a major role of miR-221 in this view.

Keywords: NASH; biliary tract cancer; bladder cancer; breast cancer; cancer; cervical cancer; demyelinating diseases; endometrial cancer; gastrointestinal cancer; glioblastoma; gynecological cancers; hematological diseases; hepatocellular carcinoma; lung cancer; melanoma; miR; miR therapeutics; miR-221; miR-221/222; miRs; microRNA; myeloma; neuropathy; ovarian cancer; pancreatic cancer; pharmacokinetics; prostate cancer; renal cell carcinoma; sarcomas; solid cancers; urogenital cancer.

Graphical abstract

Figure 1

Biogenesis of miR-221/222: miR-221/222 is a gene cluster located on chromosome Xp11.3 The gene of miR-221/222 is transcribed into primary pri-miR-221/222 by RNA polymerase II and then processed to a stem-loop precursor pre-miR-221/222 by the nuclear RNase Drosha in the nucleus. Pre-miR-221/222 is transported to the cytoplasm by the exportin-5 transporter and the endoribonuclease Dicer cleaves it into a double-stranded miR (miR duplex) and the member of the Argonaute (AGO) protein family binds mature miRs to create the RNA-induced silencing complex (RISC).

Figure 2

MiRNA-221 activity in HER2+ and Luminal BC (A) miR-221 targets PI3K-AKT-mTOR pathway in HER2+ BC. When PTEN works correctly, it helps to control the cell cycle, but when it is not functioning at full speed, cells multiply in an uncontrolled way, turning into tumor formations. PTEN inhibits the PI3K-AKT-mTOR pathway downstream of HER2, leading to resistance to various therapies like CDK 4/6 inhibitors. miR-221 facilitates tumor proliferation downregulating PTEN thus inducing EMT. miR-221 downregulates PTEN, thus inducing EMT. (B) miR-221 promotes hormonal resistance in luminal BC. IL6/Stat3 pathway drives the proliferation of CAFs and production of oncomiR-221 MVs. MVs horizontally transfer miR-221. miR-221 promotes conversion of non-CSC (ER high) into therapy-resistant CSC (ER low) by Notch3 upregulation and ER signaling suppression. This leads to CD133hi/ERlo/Notch hi CSCs.

Figure 3

miRNA-221 regulation in pancreatic ductal adenocarcinoma miRNA-221 is upregulated in pancreatic adenocarcinoma cell lines such as SW-1990, Panc-1, Miapaca-2, and Bxpc-3. When they are transfected with miR-221, mimics show an increased capacity of growth and invasion, a reduced number of G1-phase cells, and a lower apoptotic rate, which also leads to a downregulation of tumor-suppressor genes, such as pTEN, p27kip1, p57kip2, and PUMA. On the other hand, when miR-221 levels are reduced, TIMP2 expression is increased. TIMP2 inhibits MMP2 and MMP9, which are involved in cell proliferation.

Figure 4

Models of sorafenib reistance in HCC (A) miR-221 role in HCC proliferation and sorafenib resistance. Sorafenib non-responder nodules show higher levels of miR-221. (B) miR-221 inhibition in HCC overcomes sorafenib resistance. In mice treated with sorafenib, miR-221 levels correlated with tumor growth and drug resistance. Created with BioRender.com.

Figure 5

Different pathways involved in sarcomas carcinogenesis Up- or downregulation of miR-221 can cause different effects in terms of oncogenesis or oncosuppression. In osteosarcomas, upregulation of miR-221 activates P-AKT, AKT, and BCL-2 as well as inhibiting FBXW11, which in turn upregulates Wnt. PTEN and PP2R2A upregulation is also induced by miR-221 together with cisplatin resistance; downregulation of miR-221 upregulates CDKN1B27, Caspase-3, and BAX, and downregulates BCL-2, Cyclins D1 and E, SNAIL, and TWIST1, determining oncosuppression. Downregulation of miR-221 also causes angiogenesis in Kaposi sarcoma and activates CCND2, CDK6, and ERBB3 in alveolar rhabdomyosarcoma. ↑, upregulation; ↓, downregulation.

Figure 6

Main pathways involving miR-221 in GBM miR-221 inhibits SOCS3 and PTEN and promotes STAT and AKT activity, inducing cell proliferation.

Figure 7

miR-221 deregulation in non-alcoholic steatohepatitis (A) Implication of miR-221 in the pathogenesis of NAFLD. miR-221 is upregulated in NASH. Plasma levels of miR-221 have been found to be significantly correlated with the severity of NASH-induced liver injury. (B) miR-221 involved in the interaction between hepatocytes and hepatic stellate cells (HSCs). Chronic liver damage and inflammatory signals are the main cause of the HSC activated state that induces hepatic fibrogenesis. miR-221 is expressed in hepatocytes in HSC, and is secreted into the bloodstream with a potential role of a biomarker in this disease stage.

Figure 8

Deregulated expression of miR-221 in demyelinating diseases (A) The role of miR-221 in SC myelination induced through NGF1-A-binding protein-1 downregulation. (B) The role of miR-221 in schwannoma pathogenesis acting in both silencing LASS2 protein and inhibiting apoptosis. DRG, dorsal root ganglion; SCs, Schwann cells; LASS2, longevity assurance homolog 2 protein.