Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; Departments of Cell Systems & Anatomy, School of Medicine, University of Texas Health Science Center at San Antonio, TX, USA.
Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; Departments of Cell Systems & Anatomy, School of Medicine, University of Texas Health Science Center at San Antonio, TX, USA; Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200126, China.
Cell Signal. 2022 Apr;92:110278. doi: 10.1016/j.cellsig.2022.110278. Epub 2022 Feb 5.
Hedgehog signaling pathway has been previously elucidated to be inappropriately activated in many human cancers, including ovarian and breast cancer. However, mechanistic contribution of GLI3, one of the terminal effectors of the pathway, to ovarian and mammary cancer development is underexplored. In this study, we investigated whether GLI3 is necessary for the growth and migration of ovarian and breast cancer cells and further explored the underlying mechanism of GLI3-mediated oncogenesis. We report that GLI3 knockdown inhibited growth and migration of androgen receptor (AR)-positive ovarian and breast cancer cells, but not AR-negative ovarian and breast cancer cells. Furthermore, knockdown of AR expression was effective in inhibiting the growth and migration of AR-positive ovarian and breast cancer cells in the presence of GLI3, but not in GLI3 knockdown cells. Similarly, ectopic expression of AR promoted the growth and migration of AR-negative ovarian and breast cancer cells in the presence of GLI3, but not in GLI3 knockdown cells. GLI3 and AR co-immunoprecipitated each other. GLI3 expression was negatively associated with overall survival of ovarian or breast patients whose tumors expressed a high level of AR. Our findings suggest that GLI3 and AR not only physically interact, but also are mutually dependent for their malignancy-promoting activity in ovarian and breast cancer cells. GLI3-specific inhibitors may be novel therapeutics for AR-expressing ovarian and breast cancers.
Hedgehog 信号通路在许多人类癌症中被证实过度激活，包括卵巢癌和乳腺癌。然而，该通路的终末效应物之一 GLI3 在卵巢癌和乳腺癌发生中的作用机制仍未得到充分研究。在本研究中，我们研究了 GLI3 是否对卵巢癌和乳腺癌细胞的生长和迁移是必需的，并进一步探讨了 GLI3 介导的致癌作用的潜在机制。我们报告，GLI3 敲低抑制了雄激素受体（AR）阳性的卵巢癌和乳腺癌细胞的生长和迁移，但对 AR 阴性的卵巢癌和乳腺癌细胞没有影响。此外，在存在 GLI3 的情况下，下调 AR 表达可有效抑制 AR 阳性的卵巢癌和乳腺癌细胞的生长和迁移，但在 GLI3 敲低的细胞中无效。同样，在存在 GLI3 的情况下，异位表达 AR 促进了 AR 阴性的卵巢癌和乳腺癌细胞的生长和迁移，但在 GLI3 敲低的细胞中无效。GLI3 和 AR 相互免疫沉淀。GLI3 的表达与表达高水平 AR 的卵巢或乳腺癌患者的总生存率呈负相关。我们的研究结果表明，GLI3 和 AR 不仅相互作用，而且在 AR 阳性的卵巢癌和乳腺癌细胞中对其促进恶性转化的活性也是相互依赖的。GLI3 特异性抑制剂可能是治疗表达 AR 的卵巢癌和乳腺癌的新疗法。
