Ratio of miR-196s to HOXC8 Messenger RNA Correlates with Breast Cancer Cell Migration and Metastasis

Abstract

Expression profiling has identified metastasis-associated microRNAs (miRNA) but technical limitations hinder the discovery of metastasis-suppressing miRNAs. In this study, we sought metastasis-suppressing miRNAs by functional screening. Individual miRNAs were lentivirally introduced into metastatic MDA-MB-231 breast cancer cells and analyzed for effects on cell migration, a critical step in cancer metastasis. Among 486 miRNAs screened, 14 were identified that included all of the members of the miRNA-196 family (miR-196a1, miR-196a2, and miR-196b). Enforced expression of miR-196a1/2 or miR-196b abrogated in vitro invasion and in vivo spontaneous metastasis of breast cancer cells, indicating that members of the miR-196 family are potent metastasis suppressors. We found that miR-196 inhibited the expression of transcription factor HOXC8. Functional linkage was implied by small interfering RNA-mediated knockdown of HOXC8, which suppressed cell migration and metastasis, and by ectopic expression of HOXC8, which prevented the effects of miR-196 on cell migration and metastasis. Unlike other metastasis-associated miRNAs that have been described, the expressions of miR-196 were not correlated with breast cancer cell migration or the metastatic status of clinical breast tumor specimens. Instead, we detected an excellent correlation between the ratio of miR-196 to HOXC8 messages and the migratory behavior of breast cancer cell lines as well as the metastatic status of clinical samples. Our findings identify miRNA-196s as potent metastasis suppressors and reveal that the ratio of miR-196s to HOXC8 mRNA might be an indicator of the metastatic capability of breast tumors. Cancer Res; 70(20); 7894-904.

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

“…39 Moreover, enforced expression of miR-196a reduced in vitro invasion and in vivo spontaneous metastasis of breast cancer cells. 40 In addition, overexpression of miR-196a inhibited the proliferation of human adipose tissue-derived mesenchymal stem cells while enhancing osteogenic differentiation. 41 Our results show that NPC cells become radioresistant by reducing the expression of miR--196a, and expression of miR-196a restores the sensitivity of radioresistant NPC to radiation therapy.…”

Upregulation of microRNA-337 promotes the proliferation of endometrial carcinoma cells via targeting PTEN

“…Furthermore, its expression was observed to be associated with the tumor prognosis in certain patients (20)(21)(22). It has been determined that miR-337 is a key regulator of certain oncogenes, including homeobox C8 gene and transforming growth factor-β receptor type II (23,24). Previous studies have demonstrated significantly reduced expression levels of miR-337 in pancreatic ductal adenocarcinoma tissue samples when compared with adjacent nonmalignant tissues (25).…”

Clinical significance of serum miR-196a in cervical intraepithelial neoplasia and cervical cancer

“…miR-196a downregulation can lead to HOX-B7 and BMP-4 overexpression, which may be responsible for the early steps of melanoma development (Braig et al, 2010). Li et al (2010) showed that overexpression of miR-196a or miR-196b inhibited the invasion and metastatic capacity of breast cancer cells both in vitro and in vivo, suggesting miR-196a may play a role in tumor suppression in breast cancer. This contradictory role of miR-196a in regulating cancer development is poorly understood.…”