2. Academic Validation
  3. PBLD inhibits angiogenesis via impeding VEGF/VEGFR2-mediated microenvironmental cross-talk between HCC cells and endothelial cells

PBLD inhibits angiogenesis via impeding VEGF/VEGFR2-mediated microenvironmental cross-talk between HCC cells and endothelial cells

  • Oncogene. 2022 Mar;41(13):1851-1865. doi: 10.1038/s41388-022-02197-x.
Lu Han 1 2,  Xin Lin 1,  Qun Yan 1,  Chuncai Gu 1,  Mengshu Li 1,  Lei Pan 1,  Yan Meng 1,  Xinmei Zhao 3,  Side Liu 4,  Aimin Li 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.
  • 2 Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, 510120, People's Republic of China.
  • 3 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China. xmzhao914@163.com.
  • 4 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China. liuside2011@163.com.
  • 5 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China. lam0725@163.com.
PMID: 35140333 DOI: 10.1038/s41388-022-02197-x
Abstract

Sustained anti-angiogenesis therapy increases the level of tumor hypoxia, leading to increased expression of HIF-1a, thereby contributing to the resistance to anti-angiogenesis therapy in hepatocellular carcinoma (HCC). Here, we report that phenazine biosynthesis-like domain-containing protein (PBLD) inhibits hypoxia-induced angiogenesis via ERK/HIF-1a/VEGF axis in HCC cells. Bioinformatic analysis of the TCGA database and clinical samples validation also identify a negative correlation between PBLD and angiogenesis-related genes expression including HIF-1a. Apart from the downregulation of HIF-1a/VEGF expression in HCC cells, PBLD also blocks VEGF receptor 2 (VEGFR2/KDR/Flk-1) on endothelial cells via HCC-derived exosomal miR-940. PBLD also activates TCF4 transcriptional promotion effects on miR-940 by directly interacting with it. Together, PBLD exerts an inhibitory effect on angiogenesis not only via blocking the VEGFR2/KDR/Flk-1 expression in endothelial cells, but also through downregulating HIF-1a-induced VEGF expression and secretion in HCC cells. These explorations may provide a theoretical basis for exploring new targets and strategies to overcome resistance to anti-angiogenesis therapy.

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