The Mechanism Of MicroRna Participating In The Formation Of Premetastatic Niche

Tumor metastasis or recurrence is the primary cause of mortality in cancer patients. The primary tumor can create a premetastatic niche in distant organs to facilitate the dissemination of tumor cells before metastasis. There are two important characteristics in the premetastatic niche: recruitment and aggregation of bone marrow-derived cells(BMDCs) and increased permeability of vasculature. Although primary tumor-derived secreted factors were identified which participating in the formation of premetastatic niche, it is still unclear whether local genes also contribute to this process. Numerous studies have focused on the roles of mi RNAs in tumorigenesis and tumor progression. However, the function of host-derived mi RNAs in the formation of premetastatic niche has not been explored. Through the mi RNAs microarray, we identified a mi RNA signature involving in the formation of premetastatic lungs in a B16/F10 mouse melanoma model, in which mi R-30 a, 30 b, 30 c, 30 d, and 30e(mi R-30s) were significantly attenuated. Subsequent studies proved that lung fibroblast derived mi R-30 s protected lungs from VEGFR1+ BMDCs aggregation and stabilized pulmonary vasculature. Overexpression of mi R-30 s in lungs postponed lung metastasis and extended overall survival of B16/F10 tumor-bearing mice. Further, Klf9, Nedd4 l, Rab38, Skp2, and Ugt8 a were identified as targets of mi R-30 s by a screening strategy, which were highly upregulated in premetastatic lungs. Rab38 induced lung colonization of VEGFR1+ BMDCs through modulating the secretion of CCL2, CXCL1, and VEGFA. Skp2 facilitaed pulmonary vascular permeability by regulating MMP9. Ectopic expression of Rab38 and Skp2 respectively could promote lung metastasis and decrease overall survival of B16/F10 tumor-bearing mice. The above findings illuminate a novel mechanism for the formation of premetastatic niche by host-derived mi RNAs, which not only improve our knowledge of the premetastatic niche, but provide promicing targets for anti-metastatic therapeutics.