Lee Hsiao-Chen, Chang Chao-Yuan, Huang Yung-Chi, Wu Kuan-Li, Chiang Hung-Hsing, Chang Yung-Yun, Liu Lian-Xiu, Hung Jen-Yu, Hsu Ya-Ling, Wu Yu-Yuan, Tsai Ying-Ming
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Biology (Basel). 2022 May 16;11(5):760. doi: 10.3390/biology11050760.
Lung adenocarcinoma (LUAD) still holds the most dreadful clinical outcomes worldwide. Despite advanced treatment strategies, there are still some unmet needs. Next-generation sequencing of large-scale cancer genomics discovery projects combined with bioinformatics provides the opportunity to take a step forward in meeting clinical conditions. Based on in-house and The Cancer Genome Atlas (TCGA) cohorts, the results showed decreased levels of ADAMTS1 conferred poor survival compared with normal parts. Gene set enrichment analyses (GSEA) indicated the negative correlation between ADAMTS1 and the potential roles of epithelial-mesenchymal transition (EMT), metastasis, and poor prognosis in LUAD patients. With the knockdown of ADAMTS1, A549 lung cancer cells exhibited more aggressive behaviors such as EMT and increased migration, resulting in cancer metastasis in a mouse model. The pathway interaction network disclosed the linkage of downregulated α2-macroglobulin (A2M), which regulates EMT and metastasis. Furthermore, immune components analysis indicated a positive relationship between ADAMTS1 and the infiltrating levels of multiple immune cells, especially anticancer CD4 T cells in LUAD. Notably, ADAMTS1 expression was also inversely correlated with the accumulation of immunosuppressive myeloid-derived suppressor cells and regulatory T cells, implying the downregulated ADAMTS1 mediated immune adjustment to fit the tumor survival disadvantages in LUAD patients. In conclusion, our study indicates that ADAMTS1 interacts with A2M in regulating EMT and metastasis in LUAD. Additionally, ADAMTS1 contributes to poor prognosis and immune infiltration in LUAD patients.
肺腺癌（LUAD）在全球范围内仍然具有最可怕的临床结局。尽管有先进的治疗策略，但仍存在一些未满足的需求。大规模癌症基因组学发现项目的下一代测序与生物信息学相结合，为在满足临床状况方面向前迈进提供了机会。基于内部和癌症基因组图谱（TCGA）队列，结果显示与正常组织相比，ADAMTS1水平降低与较差的生存率相关。基因集富集分析（GSEA）表明ADAMTS1与LUAD患者上皮-间质转化（EMT）、转移和不良预后的潜在作用之间呈负相关。随着ADAMTS1的敲低，A549肺癌细胞表现出更具侵袭性的行为，如EMT和迁移增加，导致小鼠模型中的癌症转移。通路相互作用网络揭示了下调的α2-巨球蛋白（A2M）的联系，A2M调节EMT和转移。此外，免疫成分分析表明ADAMTS1与多种免疫细胞的浸润水平呈正相关，尤其是LUAD中的抗癌CD4 T细胞。值得注意的是，ADAMTS1表达也与免疫抑制性髓源性抑制细胞和调节性T细胞的积累呈负相关，这意味着下调的ADAMTS1介导免疫调节以适应LUAD患者的肿瘤生存劣势。总之，我们的研究表明ADAMTS1在调节LUAD的EMT和转移中与A2M相互作用。此外，ADAMTS1导致LUAD患者预后不良和免疫浸润。
