Genome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis

Abstract

miRNA globally deregulates human carcinoma. A critical open question is how many miRNAs functionally participate in cancer development, particularly in metastasis. We systematically evaluate the capability of all known human miRNAs to regulate certain metastasis-relevant cell behaviours. To perform the high-throughput screen of miRNAs, which regulate cell migration, we developed a novel self-assembled cell microarray. Here we show that over 20 % of miRNAs have migratory regulation activity in diverse cell types, indicating a general involvement of miRNAs in migratory regulation. MiR-23b, which is downregulated in human colon cancer samples, potently mediates the multiple steps of metastasis, including tumour growth, invasion and angiogenesis in vivo . It regulates a cohort of prometastatic targets, including FZD7 or MAP3k1 . These fi ndings provide new insight into the physiological and potential therapeutic importance of miRNAs as a new class of functional modulators.

Downregulation of mir-23b in plasma is associated with poor prognosis in patients with colorectal cancer

“…Functionally, overexpression of miR-23b significantly inhibited migration, proliferation, invasion and tumor growth (17)(18)(19). In accordance with its tumor suppressor role, miR-23b has been found to be downregulated in numerous cancers (20)(21)(22)(23)(24). However, data concerning the association between the expression of miR-23b in plasma and CRC were not reported yet.…”

“…The present findings revealed that the miR-23b expression in plasma was significantly associated with TNM stage, tumor depth, distant metastasis and tumor recurrence. Similarly, low miR-23b expression associates with the development of metastases in breast cancer (40) and colon cancer lung metastasis (24). Low expression of miR-23b in plasma was significantly associated with poor overall survival and shorter recurrence-free survival in CRC patients.…”

“…miR-23b was also found to regulate transforming growth factor-β/bone morphogenetic protein signaling and affected liver stem cell differentiation (35). In colon cancer, Zhang et al demonstrated that miR-23b is downregulated in human colon cancer and mediates multiple steps of metastasis, including tumor growth, invasion and angiogenesis (24). Therefore, it was hypothesized that quantitative measuring of miR-23b in the plasma may be a promising biomarker in CRC patients.…”

“…A significantly Similarly, several studies have demonstrated that miR-23b expression is significantly downregulated in various types of tumor, including prostate, hepatocellular, bladder, endometrial carcinosarcoma and colon cancer (16,17,(20)(21)(22)(23)(24). Conversely, miR-23b is overexpressed in oral squamous cell carcinoma (36), glioma (37) and breast cancer (38,39).…”

“…To verify previous studies (24,27) that reported downregulation of miR-23b in primary CRC, RT-qPCR was used to evaluate miR-23b expression in 10 paired CRC tissues and adjacent non-cancerous tissues. Additionally, the expression levels of miR-23b in 5 human CRC cell lines, consisting of the LoVo, SW480, HCT-116, HT-29 and Caco-2 cell lines, were also analyzed by RT-qPCR.…”