SOHLH2 Suppresses Angiogenesis by Downregulating HIF1α Expression in Breast Cancer
SOHLH2 Suppresses Angiogenesis by Downregulating HIF1α Expression in Breast Cancer
复制标题
SOHLH2 通过下调乳腺癌中 HIF1α 的表达来抑制血管生成
DOI：
10.1158/1541-7786.mcr-20-0771
复制
发表时间：
2021-09-01
影响因子：
5.2
通讯作者：
Hao, Jing
中科院分区：
文献类型：
--
作者：
Cui, Weiwei;Xiao, Yunling;Hao, Jing
SOHLH2在多种肿瘤中表达下调，并参与肿瘤的生长和转移。然而，SOHLH2在肿瘤血管生成中的作用及其分子机制尚未被研究。免疫组化结果显示SOHLH2与微血管密度（MVD）、肿瘤大小、组织学分级和转移呈负相关。SOHLH2的过表达通过肿瘤细胞介导的旁分泌信号抑制人脐静脉内皮细胞（HUVEC）的血管生成行为，而SOHLH2的敲低促进HUVEC的血管生成行为。SOHLH2的异位表达显著抑制了异种移植瘤的生长和MVD，下调了缺氧诱导因子1 α（HIF 1 α）介导的促血管生成基因的表达，而SOHLH2的敲除则具有相反的结果。此外，我们发现HIF 1 α的上调逆转了SOHLH2诱导的乳腺癌血管生成抑制，而HIF 1 α的抑制剂KC 7F2。可以减弱SOHLH2沉默对血管生成的促进作用。通过染色质免疫沉淀和荧光素酶报告基因检测，我们证实SOHLH2可以直接与HIF 1 α启动子结合并抑制其转录活性。总的来说，SOHLH2通过下调HIF 1 α转录抑制乳腺癌血管生成，可能是抗血管生成治疗的潜在生物标志物。
SOHLH2 has been demonstrated the downregulation in various cancers and the involvement in tumor growth and metastasis. However, the function of SOHLH2 on tumor angiogenesis and the underlying molecular mechanisms have not been interrogated. IHC staining results revealed that SOHLH2 was negatively associated with microvessel density (MVD), tumor size, histology grade, and metastasis. Overexpression of SOHLH2 inhibited the angiogenic behavior of human umbilical vein endothelial cells (HUVEC) by a tumor cell-mediated paracrine signal, while knockdown of SOHLH2 promoted HUVEC angiogenic behavior. Ectopic SOHLH2 expression remarkably suppressed tumor growth and MVD in xenograft tumors, downregulated the expression of hypoxia inducible factor-1 alpha (HIF1 alpha)-mediated proangiogenic genes in vivo and in vitro, while knockdown of SOHLH2 had an opposite result. Furthermore, we found that upregulation of HIF1 alpha reversed SOHLH2-induced suppression of breast cancer angiogenesis, while KC7F2, the inhibitor of HIF1 alpha. could attenuate the promotion of angiogenesis by SOHLH2 silencing. Using Chromatin immunoprecipitation and luciferase reporter assays, we validated that SOHLH2 could directly bind to HIF1 alpha promoter and repress its transcriptional activity. Collectively, SOHLH2 suppresses breast cancer angiogenesis by downregulating HIF1 alpha transcription and may be a potential biomarker for anti-angiogenesis therapy.