与免疫抑制性肿瘤微环境和黑色素瘤转移相关的关键因素。
Pivotal factors associated with the immunosuppressive tumor microenvironment and melanoma metastasis.
机构信息
Department of Dermatology, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China.
Department of Pediatric Surgery, First Hospital of Jilin University, Changchun, People's Republic of China.
出版信息
Cancer Med. 2021 Jul;10(14):4710-4720. doi: 10.1002/cam4.3963. Epub 2021 Jun 22.
BACKGROUND
Considering melanoma is the deadliest malignancy among dermatoma and presently lacks effective therapies, there is an urgent need to investigate the potential mechanisms underlying melanoma metastasis and determine prospective therapeutic targets for precise treatment of melanoma.
METHOD
Hub genes in melanoma metastasis were identified by analyzing RNA-seq data (mRNA, miRNA, and lncRNA) obtained from TCGA database. Then the identified hub genes were validated in human tissues with qRT-PCR, followed by survival analysis. Competing endogenous RNAs of the hub genes were defined to clarify potential molecular mechanism of melanoma progression. Then central gene-related signaling pathways were analyzed, followed by immune cell abundance analysis in tumor microenvironment with CYTERSORTx.
RESULT
A tetrad of IL2RA, IL2RG, IFNG, and IL7R genes were determined as hub genes and verified by qRT-PCR, which were significantly associated with unfavorable prognosis in melanoma. LINC02446, LINC01857, and LINC02384 may act as competing endogenous lncRNAs of IL2RA and IL7R through absorbing their shared miR.891a.5p and miR.203b.3p. JAK-STAT signaling pathway identified as the most relevant pathway in melanoma metastasis, as well as a wealthy of genes including TNFRSF 13B, TNFRSF17, TNFRSF9, TNFRSF8, TNFRSF13C, TNFRSF11B, LAG3, NRP1, ENTPD1, NT5E, CCL21, and CCR7, may induce tumor autoimmune suppression through enhancing regulatory T-cell abundance and performance in the tumor microenvironment. And regulatory T-cell proportion was indeed critically elevated in metastatic melanoma relative to primary melanoma, as well as in highly expressed IL2RA, IL2RG, IL7R, and IFNG group than their respective counterparts.
CONCLUSION
Elevated IL2RA, IL2RG, IL7R, and IFNG expression may play a central role in promoting melanoma metastasis through up regulation of intratumoral regulatory T-cell proportion mainly by activation of JAK-STAT signaling pathway. LINC02446, LINC01857, and LINC02384 may stimulate melanoma progression by reducing tumor-protecting miR.891a.5p and miR.203b.3p. A number of identified molecules including TNFRSF13B, LAG3, NRP1, ENTPD1, NT5E, CCL21, and CCR7 can serve as future therapeutic targets in melanoma treatment.
背景
考虑到黑色素瘤是皮肤科中最致命的恶性肿瘤，目前缺乏有效的治疗方法，因此迫切需要研究黑色素瘤转移的潜在机制，并确定有前途的治疗靶点，以实现对黑色素瘤的精准治疗。
方法
通过分析 TCGA 数据库中获得的 RNA-seq 数据（mRNA、miRNA 和 lncRNA），鉴定黑色素瘤转移的枢纽基因。然后通过 qRT-PCR 在人组织中验证鉴定的枢纽基因，接着进行生存分析。定义枢纽基因的竞争性内源性 RNA，以阐明黑色素瘤进展的潜在分子机制。然后分析中心基因相关的信号通路，并通过 CYTERSORTx 分析肿瘤微环境中的免疫细胞丰度。
结果
确定了一个由 IL2RA、IL2RG、IFNG 和 IL7R 基因组成的 tetrad 作为枢纽基因，并通过 qRT-PCR 进行了验证，这些基因与黑色素瘤的不良预后显著相关。LINC02446、LINC01857 和 LINC02384 可能通过吸收它们共享的 miR.891a.5p 和 miR.203b.3p 来作为 IL2RA 和 IL7R 的竞争性内源性 lncRNA。鉴定出 JAK-STAT 信号通路是黑色素瘤转移中最相关的通路，以及包括 TNFRSF13B、TNFRSF17、TNFRSF9、TNFRSF8、TNFRSF13C、TNFRSF11B、LAG3、NRP1、ENTPD1、NT5E、CCL21 和 CCR7 在内的大量基因，可能通过增强肿瘤微环境中调节性 T 细胞的丰度和功能来诱导肿瘤自身免疫抑制。事实上，转移性黑色素瘤中调节性 T 细胞的比例明显高于原发性黑色素瘤，而在高表达 IL2RA、IL2RG、IL7R 和 IFNG 的组中，其比例明显高于各自的对照组。
结论
升高的 IL2RA、IL2RG、IL7R 和 IFNG 表达可能通过激活 JAK-STAT 信号通路主要上调肿瘤内调节性 T 细胞的比例，从而在促进黑色素瘤转移中发挥核心作用。LINC02446、LINC01857 和 LINC02384 可能通过减少肿瘤保护 miR.891a.5p 和 miR.203b.3p 来刺激黑色素瘤进展。包括 TNFRSF13B、LAG3、NRP1、ENTPD1、NT5E、CCL21 和 CCR7 在内的许多已鉴定的分子可以作为黑色素瘤治疗的未来治疗靶点。
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