Activation of miR-31 function in already-established metastases elicits metastatic regression.

Abstract

Distant metastases, rather than the primary tumors from which these lesions arise, are responsible for >90% of carcinoma-associated mortality. Many patients already harbor disseminated tumor cells in their bloodstream, bone marrow, and distant organs when they initially present with cancer. Hence, truly effective anti-metastatic therapeutics must impair the proliferation and survival of already-established metastases. Here, we assess the therapeutic potential of acutely expressing the microRNA miR-31 in already-formed breast cancer metastases. Activation of miR-31 in established metastases elicits metastatic regression and prolongs survival. Remarkably, even brief induction of miR-31 in macroscopic pulmonary metastases diminishes metastatic burden. In contrast, acute miR-31 expression fails to affect primary mammary tumor growth. miR-31 triggers metastatic regression in the lungs by eliciting cell cycle arrest and apoptosis; these responses occur specifically in metastases and can be explained by miR-31-mediated suppression of integrin-α5, radixin, and RhoA. Indeed, concomitant re-expression of these three proteins renders already-seeded pulmonary metastases refractory to miR-31-conferred regression. Upon miR-31 activation, Akt-dependent signaling is attenuated and the proapoptotic molecule Bim is induced; these effects occur in a metastasis-specific manner in pulmonary lesions and are abrogated by concurrent re-expression of integrin-α5, radixin, and RhoA. Collectively, these findings raise the possibility that intervention strategies centered on restoring miR-31 function may prove clinically useful for combating metastatic disease.

• Authors: Scott Valastyan, Amelia Chang, Nathan Benaich, Ferenc Reinhardt, Robert A Weinberg
• Journal: Genes & development (Genes Dev) Vol. 25 Issue 6 Pg. 646-59 (Mar 15 2011) ISSN: 1549-5477 [Electronic] United States
• PMID: 21406558 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Retracted Publication)

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• Cytoskeletal Proteins
• MIRN31 microRNA, human
• Membrane Proteins
• MicroRNAs
• Proto-Oncogene Proteins
• radixin
• Proto-Oncogene Proteins c-akt
• rhoA GTP-Binding Protein

Topics

• Animals
• Apoptosis (physiology)
• Apoptosis Regulatory Proteins (metabolism)
• Bcl-2-Like Protein 11
• Breast Neoplasms (physiopathology)
• Cell Cycle (physiology)
• Cell Line
• Cytoskeletal Proteins (metabolism)
• Female
• Gene Expression Regulation
• Humans
• Lung Neoplasms (secondary)
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs (metabolism)
• Neoplasm Metastasis (physiopathology, therapy)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Tumor Cells, Cultured
• rhoA GTP-Binding Protein (metabolism)