The secreted protein transforming growth factor-beta (TGFβ) plays essential roles, ranging from cell growth regulation and cell differentiation in both normal and cancer cells. In melanoma, TGFβ acts as a potent tumor suppressor in melanoma by blocking cell cycle progression and inducing apoptosis. In the present study, we found TGFβ to regulate cancer stemness in melanoma through the Smad signaling pathway. We discovered that TGFβ/Smad signaling inhibits melanosphere formation in multiple melanoma cell lines and reduces expression of the CD133+ cancer stem cell subpopulation in a Smad3-dependent manner. Using preclinical models of melanoma, we further showed that preventing Smad3/4 signaling, by means of CRISPR knockouts, promoted both tumorigenesis and lung metastasis in vivo. Collectively, our results define new functions for the TGFβ/Smad signaling axis in melanoma stem-cell maintenance and open avenues for new therapeutic approaches to this disease.
分泌蛋白转化生长因子-β（TGFβ）在正常细胞和癌细胞中均发挥着从细胞生长调控到细胞分化等多重关键作用。在黑色素瘤中，TGFβ通过阻滞细胞周期进程并诱导细胞凋亡，发挥着强大的肿瘤抑制作用。本研究发现，TGFβ通过Smad信号通路调控黑色素瘤的癌症干细胞特性。我们证实TGFβ/Smad信号通路能够抑制多种黑色素瘤细胞系中黑色素球的形成，并以Smad3依赖性方式降低CD133+癌症干细胞亚群的表达水平。通过黑色素瘤临床前模型研究，我们进一步发现利用CRISPR基因敲除技术阻断Smad3/4信号传导，可在体内同时促进肿瘤发生和肺转移。综上所述，本研究揭示了TGFβ/Smad信号轴在黑色素瘤干细胞维持中的新功能，为该疾病的治疗策略开辟了新途径。
肿瘤(癌症)患者之家