As one of the most common malignant tumors, melanoma is a serious threat to human health. More than half of melanoma patients have a BRAF mutation, and 90% of them have a BRAF(V600E) mutation. There is a targeted therapy for patients using a BRAF(V600E) inhibitor. However, no response to treatment is generally inevitable due to the heterogeneity of melanoma. Coupled with its high metastatic character, melanoma ultimately leads to poor overall survival. This study aimed to explore the possible mechanisms of melanoma metastasis and identify a more effective method for the treatment of melanoma. In this paper, we report that TCF12 expression is higher in melanoma, especially in metastatic tumors, through analyzing data from TCGA. Then, cell proliferation, colony formation, and transwell assays show that the upregulated expression of TCF12 can promote proliferation and metastasis of melanoma cells in vitro. The same result is confirmed in the subcutaneous tumor formation assay. Moreover, TGFB2 is identified as a direct downstream target of TCF12 by RNA-seq, qPCR, immunoblotting, ChIP, and a dual luciferase reporting assay. Interestingly, depletion of TCF12 can sensitize melanoma to BRAF inhibition both in vitro and in vivo. Overall, our results demonstrate that TCF12 promotes melanoma progression and can be a potential tumor therapeutic target.
作为最常见的恶性肿瘤之一，黑色素瘤严重威胁人类健康。超过半数的黑色素瘤患者存在BRAF基因突变，其中90%为BRAF(V600E)突变。针对此类患者可采用BRAF(V600E)抑制剂进行靶向治疗。然而，由于黑色素瘤的异质性，治疗无响应往往难以避免。加之其高转移特性，黑色素瘤最终导致患者总体生存率低下。本研究旨在探索黑色素瘤转移的可能机制，并寻求更有效的治疗方法。通过分析TCGA数据库数据，本研究发现TCF12在黑色素瘤中表达升高，尤其在转移性肿瘤中更为显著。细胞增殖、克隆形成及Transwell实验表明，TCF12表达上调可促进黑色素瘤细胞的体外增殖和转移能力。皮下成瘤实验进一步验证了这一结果。通过RNA测序、qPCR、免疫印迹、染色质免疫共沉淀及双荧光素酶报告基因实验，本研究确定TGFB2是TCF12的直接下游靶点。值得注意的是，在体外和体内实验中，敲低TCF12表达均能增强黑色素瘤对BRAF抑制剂的敏感性。综上所述，本研究证实TCF12能够促进黑色素瘤进展，并可能成为潜在的肿瘤治疗靶点。
TCF12 Activates TGFB2 Expression to Promote the Malignant Progression of Melanoma
肿瘤(癌症)患者之家