Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
Department of Dermatology, The First Affiliated Hospital, Shihezi University, Shihezi, 832061, Xinjiang, China.
Sci Rep. 2024 Nov 1;14(1):26288. doi: 10.1038/s41598-024-76477-9.
Melanoma is the most dangerous form of skin cancer. Hence, a better understanding of molecular mechanisms in melanoma pathogenesis is urgently needed, which provides a new insight into the therapy of melanoma. DTL gene is screened out in melanoma pathogenesis by integrated bioinformatics analysis, and its expression is validated in the tissue and cell samples of melanoma. Forced DTL expression facilitates the proliferation, invasion, migration and EMT of melanoma cells, while DTL knockdown suppresses the biological behavior of melanoma cells. In addition, DTL promotes the malignancy of melanoma in vivo. Mechanistically, BUB1 is the crucial downstream target of DTL. Reduced DTL expression suppresses BUB1 expression, while enhanced DTL expression induces BUB1 upregulation. Rescue experiments showed that growing and migrating of melanoma cells induced by DTL are partially impaired by BUB1 inhibition. In addition, the expression of phosphorylated ERK (p-ERK) and the downstream transcription factor E2F1 are reduced when DTL expression is blocked. Meanwhile, BUB1 levels are decreased when the expression of p-ERK or E2F1 is repressed. Notably, the growth and migration of melanoma cells by inhibition of ERK and knockdown of E2F1 was rescued by overexpressing BUB1. DTL gene may be a prognosis marker and represent a unique potential target for melanoma patients. DTL supports the biologically malignant activity of melanoma cells via the ERK/E2F1/BUB1 axis.
黑色素瘤是最危险的皮肤癌形式。因此，迫切需要更好地了解黑色素瘤发病机制中的分子机制，这为黑色素瘤的治疗提供了新的见解。通过综合生物信息学分析筛选出黑色素瘤发病机制中的 DTL 基因，并在黑色素瘤的组织和细胞样本中验证其表达。强制表达 DTL 可促进黑色素瘤细胞的增殖、侵袭、迁移和 EMT，而 DTL 敲低则抑制黑色素瘤细胞的生物学行为。此外，DTL 促进黑色素瘤在体内的恶性进展。在机制上，BUB1 是 DTL 的关键下游靶标。降低 DTL 表达可抑制 BUB1 的表达，而增强 DTL 表达则诱导 BUB1 的上调。挽救实验表明，DTL 诱导的黑色素瘤细胞的生长和迁移部分被 BUB1 抑制所损害。此外，当阻断 DTL 的表达时，磷酸化 ERK（p-ERK）和下游转录因子 E2F1 的表达减少。同时，当抑制 p-ERK 或 E2F1 的表达时，BUB1 水平降低。值得注意的是，通过抑制 ERK 和敲低 E2F1 抑制黑色素瘤细胞的生长和迁移，通过过表达 BUB1 得到挽救。DTL 基因可能是一种预后标志物，并代表了黑色素瘤患者独特的潜在治疗靶点。DTL 通过 ERK/E2F1/BUB1 轴支持黑色素瘤细胞的生物学恶性活性。
