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Article

BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma

1
Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
2
Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
3
Department of Gastroenterology, Kanazawa University Hospital, Kanazawa 9208641, Japan
4
Department of General Medicine, Kanazawa University Hospital, Kanazawa 9208641, Japan
*
Authors to whom correspondence should be addressed.
Academic Editor: Tomohiko Fukuda
Int. J. Mol. Sci. 2022, 23(3), 1475; https://doi.org/10.3390/ijms23031475
Received: 30 December 2021 / Revised: 21 January 2022 / Accepted: 25 January 2022 / Published: 27 January 2022
(This article belongs to the Special Issue BMP Signaling and TGF-β Family in Cancer Development)
Since hepatocellular carcinoma (HCC) is a typical hypervascular malignant tumor with poor prognosis, targeting angiogenesis is an important therapeutic strategy for advanced HCC. Involvement of bone morphologic protein 9 (BMP9), a transforming growth factor-beta superfamily member, has recently been reported in the development of liver diseases and angiogenesis. Here, we aimed to elucidate the role of BMP9 signaling in promoting HCC angiogenesis and to assess the antiangiogenic effect of BMP receptor inhibitors in HCC. By analyzing HCC tissue gene expression profiles, we found that BMP9 expression was significantly correlated with angiogenesis-associated genes, including HIF-1α and VEGFR2. In vitro, BMP9 induced HCC cell HIF-1α/VEGFA expression and VEGFA secretion. Silencing of the inhibitor of DNA-binding protein 1 (ID1), a transcription factor targeted by BMP9 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression and VEGFA secretion, resulting in decreased human umbilical vein endothelial cell (HUVEC) lumen formation. BMP receptor inhibitors, which inhibit BMP9-ID1 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression, VEGFA secretion, and HUVEC lumen formation. In vivo, the BMP receptor inhibitor LDN-212854 successfully inhibited HCC tumor growth and angiogenesis by inhibiting BMP9-ID1 signaling. In summary, BMP9-ID1 signaling promotes HCC angiogenesis by activating HIF-1α/VEGFA expression. Thus, targeting BMP9-ID1 signaling could be a pivotal therapeutic option for advanced HCC. View Full-Text
Keywords: BMP9-ID1 signaling; angiogenesis; HIF-1α; VEGFA; hepatocellular carcinoma; BMP receptor inhibitor BMP9-ID1 signaling; angiogenesis; HIF-1α; VEGFA; hepatocellular carcinoma; BMP receptor inhibitor
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MDPI and ACS Style

Chen, H.; Nio, K.; Tang, H.; Yamashita, T.; Okada, H.; Li, Y.; Doan, P.T.B.; Li, R.; Lv, J.; Sakai, Y.; Yamashita, T.; Mizukoshi, E.; Honda, M.; Kaneko, S. BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2022, 23, 1475. https://doi.org/10.3390/ijms23031475

AMA Style

Chen H, Nio K, Tang H, Yamashita T, Okada H, Li Y, Doan PTB, Li R, Lv J, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S. BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma. International Journal of Molecular Sciences. 2022; 23(3):1475. https://doi.org/10.3390/ijms23031475

Chicago/Turabian Style

Chen, Han, Kouki Nio, Hong Tang, Taro Yamashita, Hikari Okada, Yingyi Li, Phuong T.B. Doan, Ru Li, Junyan Lv, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Honda, and Shuichi Kaneko. 2022. "BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma" International Journal of Molecular Sciences 23, no. 3: 1475. https://doi.org/10.3390/ijms23031475

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