Human UTP14a promotes angiogenesis through upregulating PDGFA expression in colorectal cancer.

ABSTRACT

The human UTP14a (hUTP14a) promotes degradation of p53 and RB. Moreover, hUTP14a stabilizes c-Myc and is associated with the metastasis of human colorectal cancer (CRC). Angiogenesis plays a key role in tumor growth and metastasis. However, how hUTP14a regulates angiogenesis is unknown. Here, we show that nucleolar expression of hUTP14a is positively associated with higher microvascular density (MVD) in the CRC tumor tissues. The conditioned medium (CM) from CRC cells HCT116 and LoVo with hUTP14a knockdown impairs tube formation and migration of human umbilical vein endothelial cells (HUVECs). RNA-seq analysis indicates that hUTP14a might regulate expression of angiogenic factors in tumor cells. We further demonstrate that hUTP14a upregulates transcription and secretion of platelet-derived growth factor subunit A (PDGFA) in CRC cells. The CRC-CM derived from hUTP14a-depleted cells inhibits the PDGFA-mediated signaling pathway and induces apoptosis in HUVECs. In contrast, the CRC-CM derived from cells expressing Flag-hUTP14a activates the PDGFA-mediated signaling pathway in HUVECs. Importantly, the CRC-CM derived from Flag-hUTP14a-expressing cells promotes angiogenesis in HUVECs, which is counteracted by PDGFR inhibitor imatinib. We thus demonstrate that hUTP14a promotes angiogenesis by upregulating expression and secretion of PDGFA. The in vivo Matrigel plug assay shows that depletion of hUTP14a dramatically decreased MVD in mice xenografts. Collectively, we demonstrate that hUTP14a promotes angiogenesis in CRC and indicate that targeting hUTP14a might improve the prognosis of the hUTP14a-expressing CRC patients.