Emerging roles and mechanisms of microRNA‑222‑3p in human cancer (Review)

Abstract

MicroRNAs (miRNAs/miRs) are a class of small non‑coding RNAs that maintain the precise balance of various physiological processes through regulating the function of target mRNAs. Dysregulation of miRNAs is closely associated with various types of human cancer. miR‑222‑3p is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in tumor occurrence and progression. miR‑222‑3p in human biofluids, such as urine and plasma, may be a potential biomarker for the early diagnosis of tumors. In addition, miR‑222‑3p acts as a prognostic factor for the survival of patients with cancer. The present review first summarizes and discusses the role of miR‑222‑3p as a biomarker for diverse types of cancers, and then focuses on its essential roles in tumorigenesis, progression, metastasis and chemoresistance. Finally, the current understanding of the regulatory mechanisms of miR‑222‑3p at the molecular level are summarized. Overall, the current evidence highlights the crucial role of miR‑222‑3p in cancer diagnosis, prognosis and treatment.

Keywords: miR‑222‑3p; biomarker; cell signaling pathway; exosome; therapeutic target.

Figure 1

Prognostic value of miR-222-3p in human cancer. miR-222-3p expression in different types of human cancer was analyzed from The Cancer Genome Atlas database. Patients were divided into two groups according to the expression levels of miR-222-3p, either lower or higher than the mean value. The Kaplan-Meier analysis method was used for survival analysis using the software GraphPad Prism 7. Log-rank P<0.05 was considered to indicate a statistically significant difference. Considering the mid- and late-stage crossovers, the weighted method of Cramer-von Mises testing was used. (A) Seven types of cancer in which the overall survival of patients was significantly associated with miR-222-3p expression. (B and C) Eleven types of cancer in which the overall survival of patients was not significantly associated with miR-222-3p expression. miR, microRNA.

Figure 2

Emerging roles and mechanisms of miR-222-3p in human cancer. miR-222-3p can directly or indirectly regulate multiple downstream pathways, such as PI3K/AKT, PTEN, JAK/STAT, TRPS1/ZEB1 and EMT, between which crosstalks usually exist, thus constituting a complex signaling network. Additionally, miR-222-3p can extensively regulate multiple cell functions, including differentiation, proliferation, apoptosis, invasion, metastasis and metabolism modulation via targeting gene expression at the post-transcriptional level. Furthermore, miR-222-3p serves an important role as either a tumor suppressor or an oncogene in different types of cancer. Dysregulated miR-222-3p expression contributes to drug resistance and has been emphasized as a new drug target. In addition, miR-222-3p expression can be regulated via both transcriptional factors and epigenetic factor-induced mechanisms in cancer cells. AR, androgen receptor; DOX, doxycycline; EMT, epithelial-mesenchymal transition; E-cad, E-cadherin; ERa, estrogen receptor α; FOXP2, forkhead box protein P2; GNAI2, G protein α inhibiting activity polypeptide 2; HIPK2, homeodomain-interacting protein kinases 2; HMGA1, high mobility group AT-hook 1; lncR GAS5, long non-coding RNA growth arrest-specific 5; MDM2, murine double minute 2; miR, microRNA; MMP, matrix metalloproteinase; PI3K, phosphoinositide 3-kinase; PPP2R2A, phosphatase 2A subunit B; PR, progesterone receptor; PTEN, phosphatase and tensin homology deleted on chromosome ten; SOCS3, suppressor cytokine signaling 3; YAP, Yes-associated protein; 5-FU, 5-fluorouracil.