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

Abstract

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.

Schizophrenia endothelial cells exhibit higher permeability and altered angiogenesis patterns in patient-derived organoids

“…Significantly altered pathways included diverse types of cascades that are linked to endothelial cell generation or function such as ElF2, ID1, and mTOR signaling. EIF2 signaling is comprised of several endothelial cell transcription factors and regulates both cell cycle progression and angiogenesis [ 55 – 57 ], while ID1 signaling activates HIF-1a and VEGF-A to promote tumor angiogenesis in certain cancers [ 58 ]. Concurrently, the mTOR pathway in endothelial cells has been shown to regulate angiogenic sprouting, migration, cytoskeleton reorganization, and signaling events impacting matrix adhesion [ 59 , 60 ].…”

“…4c ) . Intriguingly, ID1 signaling was recently shown to activate VEGF-A to promote angiogenesis [ 58 ]. Taken together, in our organoid system there is substantial evidence of increased angiogenic potential in SCZ compared to CTRL, a possible effect of enriched ID1, ElF2 and mTOR pathways.…”

Expression of Bone Morphogenetic Protein 14 in Liver Disease and Cancer

“…Furthermore, BMP9 has been shown to promote the growth of HCC cell lines [50]. Another study found that BMP9 induces angiogenesis via the ID1 signaling axis, and therefore acts as a pro-tumorigenic [51].…”

“…Livers 2023, 3, FOR PEER REVIEW 9 lines [50]. Another study found that BMP9 induces angiogenesis via the ID1 signaling axis, and therefore acts as a pro-tumorigenic [51]. Together, these previous studies have indicated the complexity of the BMP system in diseased livers, since individual members of the large BMP protein family can even have opposite effects on critical pathological steps of chronic liver diseases.…”

Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies

“…VEGFR2 is expressed in almost all ECs and is activated by binding of VEGFA, B, C, or D. VEGFA is the most critical ligand among these VEGFs. The binding of VEGFA/VEGFR2 leads to a phosphorylation cascade that triggers downstream cellular signaling pathways, including the PI3K/AKT and RAF/MAPK pathways, thereby resulting in ECs proliferation and migration, and the formation of branches of new blood vessels necessary for rapid tumor growth and metastasis 14 , 15 . Furthermore, the permeability of the newly formed vessels usually increases, thus forming areas of high interstitial pressure and severe hypoxia or necrosis, which further promote HCC progression and angiogenesis 16 .…”