PDF(Pubmed)
Abstract：
Cutaneous melanoma (CM) is an aggressive form of skin cancer with limited treatment options for advanced stages. Prognostic markers that accurately predict patients\' outcomes and guide therapeutic strategies are crucial for improving melanoma management. SETD2 (SET Domain-Containing Protein 2), a histone methyltransferase involved in chromatin remodeling and gene regulation, has recently emerged as a tumor suppressor. Its dysfunction is involved in oncogenesis in some cancers, but little is known about its functions in progression and therapeutic response of melanoma.
RNA-seq and clinical data from public database were used to evaluate the survival analysis, gene set enrichment, IC50 of therapeutics and immunotherapy response. SETD2 knock-out A375 cell line (A375SETD2ko) was developed by Crispr/cas9 and CCK-8 analysis and nude mice used to evaluate the proliferation and invasion of melanoma cells in vitro and in vivo, while Western blotting tested the MMR-related protein.
SETD2 was commonly down-regulated in melanoma samples which demonstrated an unfavorable survival. Cells without SETD2 expression tend to have a more progressive and invasive behavior, with resistance to chemotherapy. However, they are more sensitive to tyrosine kinase inhibitors (TKIs). They also exhibit inflamed features with lower TIDE (Tumor Immune Dysfunction and Exclusion) score and higher tumor mutation burden (TMB), showing that these patients may benefit from immunotherapy.
This study revealed that SETD2 dysfunction in melanoma implied a poor prognosis and chemotherapy resistance, but highly sensitive to TKIs and immunotherapy, highlighting the prognostic and therapeutic value of SETD2 in cutaneous melanoma.
RNA-seq and clinical data from public database were used to evaluate the survival analysis, gene set enrichment, IC50 of therapeutics and immunotherapy response. SETD2 knock-out A375 cell line (A375SETD2ko) was developed by Crispr/cas9 and CCK-8 analysis and nude mice used to evaluate the proliferation and invasion of melanoma cells in vitro and in vivo, while Western blotting tested the MMR-related protein.
SETD2 was commonly down-regulated in melanoma samples which demonstrated an unfavorable survival. Cells without SETD2 expression tend to have a more progressive and invasive behavior, with resistance to chemotherapy. However, they are more sensitive to tyrosine kinase inhibitors (TKIs). They also exhibit inflamed features with lower TIDE (Tumor Immune Dysfunction and Exclusion) score and higher tumor mutation burden (TMB), showing that these patients may benefit from immunotherapy.
This study revealed that SETD2 dysfunction in melanoma implied a poor prognosis and chemotherapy resistance, but highly sensitive to TKIs and immunotherapy, highlighting the prognostic and therapeutic value of SETD2 in cutaneous melanoma.
摘要：
背景：皮肤黑素瘤（CM）是一种侵袭性形式的皮肤癌，晚期治疗选择有限。准确预测患者预后和指导治疗策略的预后标志物对于改善黑色素瘤管理至关重要。SETD2（含有SET结构域的蛋白质2），参与染色质重塑和基因调控的组蛋白甲基转移酶，最近已经成为一种肿瘤抑制因子。它的功能障碍与一些癌症的发生有关，但对其在黑色素瘤的进展和治疗反应中的功能知之甚少。
方法：RNA-seq和来自公共数据库的临床数据用于评估生存分析，基因集富集，治疗和免疫疗法反应的IC50。SETD2敲除A375细胞系（A375SETD2ko）是通过Crispr/cas9和CCK-8分析开发的，用于评估体外和体内黑色素瘤细胞的增殖和侵袭的裸鼠，而Western印迹检测了MMR相关蛋白。
结果:在黑素瘤样品中SETD2通常下调,这证明了不利的存活。没有SETD2表达的细胞倾向于具有更进行性和侵入性的行为，对化疗有抵抗力.然而,它们对酪氨酸激酶抑制剂（TKIs）更敏感。它们还表现出炎症特征，具有较低的TIDE（肿瘤免疫功能障碍和排除）评分和较高的肿瘤突变负担（TMB），表明这些患者可能受益于免疫疗法。
结论：这项研究表明，黑色素瘤的SETD2功能障碍意味着预后不良和化疗耐药，但对TKIs和免疫疗法高度敏感，强调SETD2在皮肤黑色素瘤中的预后和治疗价值。
方法：RNA-seq和来自公共数据库的临床数据用于评估生存分析，基因集富集，治疗和免疫疗法反应的IC50。SETD2敲除A375细胞系（A375SETD2ko）是通过Crispr/cas9和CCK-8分析开发的，用于评估体外和体内黑色素瘤细胞的增殖和侵袭的裸鼠，而Western印迹检测了MMR相关蛋白。
结果:在黑素瘤样品中SETD2通常下调,这证明了不利的存活。没有SETD2表达的细胞倾向于具有更进行性和侵入性的行为，对化疗有抵抗力.然而,它们对酪氨酸激酶抑制剂（TKIs）更敏感。它们还表现出炎症特征，具有较低的TIDE（肿瘤免疫功能障碍和排除）评分和较高的肿瘤突变负担（TMB），表明这些患者可能受益于免疫疗法。
结论：这项研究表明，黑色素瘤的SETD2功能障碍意味着预后不良和化疗耐药，但对TKIs和免疫疗法高度敏感，强调SETD2在皮肤黑色素瘤中的预后和治疗价值。
