KSHV MicroRNAs Repress Tropomyosin 1 and Increase Anchorage-Independent Growth and Endothelial Tube Formation.
Kaposi's sarcoma (KS) is characterized by highly vascularized spindle-cell tumors induced after infection of endothelial cells by Kaposi's sarcoma-associated herpesvirus (KSHV). In KS tumors, KSHV expresses only a few latent proteins together with 12 pre-microRNAs. Previous microarray and proteomic studies predicted that multiple splice variants of the tumor suppressor protein tropomyosin 1 (TPM1) were targets of KSHV microRNAs. Here we show that at least two microRNAs of KSHV, miR-K2 and miR-K5, repress protein levels of specific isoforms of TPM1. We identified a functional miR-K5 binding site in the 3' untranslated region (UTR) of one TPM1 isoform. Furthermore, the inhibition or loss of miR-K2 or miR-K5 restores expression of TPM1 in KSHV-infected cells. TPM1 protein levels were also repressed in KSHV-infected clinical samples compared to uninfected samples. Functionally, miR-K2 increases viability of unanchored human umbilical vein endothelial cells (HUVEC) by inhibiting anoikis (apoptosis after cell detachment), enhances tube formation of HUVECs, and enhances VEGFA expression. Taken together, KSHV miR-K2 and miR-K5 may facilitate KSHV pathogenesis.
HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Philippe
P
Kieffer-Kwon
HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Christine
C
Happel
HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Thomas S
TS
Uldrick
HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Dhivya
D
Ramalingam
HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Joseph M
JM
Ziegelbauer
D020413:3' Untranslated Regions; D023102:Anoikis / Q000235:genetics; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism* / Q000821:virology; D005786:Gene Expression Regulation; D023061:Gene Order; D019288:Herpesvirus 8, Human / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008970:Molecular Weight; D020033:Protein Isoforms; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral; D014335:Tropomyosin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D020413:3' Untranslated Regions; D035683:MicroRNAs; D020033:Protein Isoforms; D012333:RNA, Messenger; D012367:RNA, Viral; C490775:TPM1 protein, human; D014335:Tropomyosin