Hedyotis diffusa Willd extract suppresses Sonic hedgehog signaling leading to the inhibition of colorectal cancer angiogenesis
Hedyotis diffusa Willd extract suppresses Sonic hedgehog signaling leading to the inhibition of colorectal cancer angiogenesis
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DOI：
10.3892/ijo.2012.1753
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发表时间：
2013-02-01
影响因子：
5.2
通讯作者：
Peng, Jun
中科院分区：
文献类型：
--
作者：
Lin, Jiumao;Wei, Lihui;Peng, Jun
Sonic hedgehog（SHH）信号通路促进血管生成，促进包括结直肠癌（CRC）在内的多种恶性肿瘤的生长和进展，因此成为肿瘤化疗的一个有前途的靶点。白花蛇舌草（Hedyotis diffusa Willd，HDW）是我国著名的传统中草药，在临床上用于治疗多种肿瘤。最近，我们报道了HDW可以通过抑制STAT 3通路在体内和体外抑制结直肠癌的生长。此外，我们证明了HDW在体外的抗血管生成活性。为了进一步阐明HDW的杀肿瘤活性的机制，通过使用CRC小鼠异种移植模型，我们评估了HDW的乙醇提取物（EEHDW）对肿瘤血管生成的体内作用，并研究了潜在的分子机制。我们发现EEHDW能显著降低肿瘤内微血管密度（MVD），表明其在体内具有抗血管生成的活性。EEHDW抑制CRC异种移植肿瘤中SHH信号传导的激活，因为它显著降低了SHH通路关键介质的表达。EEHDW处理抑制关键SHH信号传导靶基因VEGF-A及其特异性受体VEGFR 2的表达。综上所述，我们首次提出白花蛇舌草通过抑制SHH介导的肿瘤血管生成来抑制体内结直肠癌生长。
Sonic hedgehog (SHH) signaling pathway promotes the process of angiogenesis, contributing to the growth and progression of many human malignancies including colorectal cancer (CRC), which therefore has become a promising target for cancer chemotherapy. Hedyotis diffusa Willd (HDW), as a well-known traditional Chinese herbal medicine, has long been used in China for the clinic treatment of various cancers. Recently, we reported that HDW can inhibit colorectal cancer growth in vivo and in vitro via suppression of the STAT3 pathway. In addition, we demonstrated the anti-angiogenic activity of HDW in vitro. To further elucidate the mechanism of the tumoricidal activity of HDW, by using a CRC mouse xenograft model we evaluated the in vivo effect of the ethanol extract of HDW (EEHDW) on tumor angiogenesis, and investigated the underlying molecular mechanisms. We found that EEHDW could significantly reduce intratumoral microvessel density (MVD), indicating its activity of antitumor angiogenesis in vivo. EEHDW suppressed the activation of SHH signaling in CRC xenograft tumors since it significantly decreased the expression of key mediators of SHH pathway. EEHDW treatment inhibited the expression of the critical SHH signaling target gene VEGF-A as well as its specific receptor VEGFR2. Taken together, we propose for the first time that Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of SHH-mediated tumor angiogenesis.