MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2

Abstract

MicroRNAs (miRNAs) have emerged as key players in cancer progression and metastatic initiation yet their importance in regulating prostate cancer (PCa) metastasis to bone has begun to be appreciated. We employed multimodal strategy based on in-house PCa clinical samples, publicly available TCGA cohorts, a panel of cell lines, in silico analyses, and a series of in vitro and in vivo assays to investigate the role of miR-466 in PCa. Expression analyses revealed that miR-466 is under-expressed in PCa compared to normal tissues. Reconstitution of miR-466 in metastatic PCa cell lines impaired their oncogenic functions such as cell proliferation, migration/invasion and induced cell cycle arrest, and apoptosis compared to control miRNA. Conversely, attenuation of miR-466 in normal prostate cells induced tumorigenic characteristics. miR-466 suppressed PCa growth and metastasis through direct targeting of bone-related transcription factor RUNX2. Overexpression of miR-466 caused a marked downregulation of integrated network of RUNX2 target genes such as osteopontin, osteocalcin, ANGPTs, MMP11 including Fyn, pAkt, FAK and vimentin that are known to be involved in migration, invasion, angiogenesis, EMT and metastasis. Xenograft models indicate that miR-466 inhibits primary orthotopic tumor growth and spontaneous metastasis to bone. Receiver operating curve and Kaplan–Meier analyses show that miR-466 expression can discriminate between malignant and normal prostate tissues; and can predict biochemical relapse. In conclusion, our data strongly suggests miR-466-mediated attenuation of RUNX2 as a novel therapeutic approach to regulate PCa growth, particularly metastasis to bone. This study is the first report documenting the anti-bone metastatic role and clinical significance of miR-466 in prostate cancer.

MicroRNA-466 (miR-466) functions as a tumor suppressor and prognostic factor in colorectal cancer (CRC)

“…In this study, we showed that the expression of miR-466 was downregulated in CRC compared to matched adjacent normal tissues, suggesting that miR-466 may be associated with the progression and development of CRC. Similar results were reported on the role of miR-466 in PC [11].…”

“…Our results showed that the increased expression of miR-466 suppressed the proliferation, migration and invasion as well as induced apoptosis in CRC cells. Similar results were also reported in highly metastatic PC cells [11]. Overall, our results indicated that the overexpression of miR-466 impaired the oncogenic function in CRC cells, which may also explain the positive association between miR-466 downregulation and the tumor size, TNM stage, metastasis, and poor outcome.…”

“…A recent study showed that miR-466 was underexpressed in prostate cancer (PC) and that the restoration of miR-466 expression in metastatic PC cell lines led to the impaired oncogenic functions, induced cell cycle arrest, and apoptosis in cancer cells. Moreover, miR-466 exerted the anti-tumor effect through direct targeting of bone-related transcription factor RUNX2 [11]. On the contrary, the occurrence and development of cervical cancer were closely associated with increased expression of miR-466 [12].…”

The role of microRNAs in prostate cancer migration, invasion, and metastasis

“…Expression analyses demonstrated that miR‐466 was downmodulated in PCa relative to normal tissues. Newly Colden et al () dissected that in vitro upmodulation of miR‐466 in metastatic PCa cell lines diminished oncogenic features like cell proliferation, migration/invasion, and increased cell cycle arrest as well as apoptosis of tumor cells than control miRNA. Contrarily, depletion of miR‐466 in normal PCa cell lines increased tumorigenic behaviors.…”

Implications of microRNA dysregulation in the development of prostate cancer

“…It has been reported that miR-466 directly targeted RUNX2, which induced downregulation of RUNX-target genes involved in migration, invasion, EMT and metastasis. Overexpression of miR-466 in PC3 orthotopic xenografts greatly reduced the number of spontaneous bone metastases and improved mice overall survival (Colden et al 2017).…”