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Deubiquitinase UCHL5 is elevated and associated with a poor clinical outcome in lung adenocarcinoma (LUAD).

ABSTRACT: Lung cancer is one of the most common malignant tumors in the world, with a high rate of malignancy and mortality. Seeking new biomarkers and potential drug targets is urgent for effective treatment of the disease. Deubiquitinase UCHL5/UCH37, as an important component of the 26S proteasome, plays critical roles in ubiquitinated substrate degradation. Although previous studies have shown that UCHL5 promotes tumorigenesis, its role in lung cancer remains largely unknown. In this study, we evaluated the expression and clinical significance of UCHL5 in non-small cell lung cancer (NSCLC). The results demonstrated that the UCHL5 expression level was significantly upregulated in NSCLC tissues compared with the adjacent noncancerous tissues. The level of UCHL5 was associated with tumor size, lymph node invasion, TNM stage and malignant tumor history in patients with lung adenocarcinoma (LUAD). Importantly, high UCHL5 expression predicted a poor overall survival (OS) and a poor disease-free survival (DFS) in patients with LUAD. Univariate regression analysis showed that tumor size, lymph node invasion, TNM stage and UCHL5 expression were associated with OS and DFS in patients with LUAD. The multivariate analysis indicated that the UCHL5 expression level was an independent prognostic factor for OS (HR=1.171, 95% CI=1.052-1.303) and DFS (HR=1.143, 95% CI=1.031-1.267) in these patients. UCHL5 knockdown in LUAD cells significantly inhibited cell proliferation and reduced the expression of key cell cycle proteins. These findings indicate that UCHL5 may serve as a potential prognostic marker and a new therapeutic target for patients with LUAD.

SUBMITTER: Zhang J

PROVIDER: S-EPMC7545677 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundImmune checkpoint inhibitors (ICIs) emerge as the first-line treatment of lung adenocarcinoma (LUAD); selection of subpopulations acquiring clinical benefit is required. Associations between epigenetic modulation of tumor microenvironment (TME) and clinical outcome are far from clear. We focused on immune-related genes closely regulated by DNA methylation to identify the potential clinical outcome indicators.MethodsWe systematically calculated immunophenotype score (IMpS) and classified immunophenotypes based on seven TME features in three independent cohorts. The overlapping of differential expressed genes and methylated probes targeted genes was regarded as genes closely regulated by DNA methylation. Then, probe/gene pairs which highly correlated with each other and IMpS were identified and named as immune-related probe/gene pairs (mIMg). Prognostic mIMg were selected and verified in seven independent validation cohorts.ResultsThree immune phenotypes were clustered, and similar results were obtained in the three independent training cohorts. C2 displayed as an immunologically hot phenotype, whereas C3 corresponded with immunologically cold phenotype. Average methylation level was decreased from C2 to C3 (C2 > C1 > C3). Similarly, ICIs nonresponders showed global hypo-methylation compared with responders. Genes in mIMg were mainly enriched, especially in T-cell receptor activation, and repressed in noninflamed TME by hyper-methylation. Among mIMg, low expression and hyper-methylation of CD247, LCK, and PSTPIP1 were risk factors of overall survival (OS). ICIs nonresponders were more likely to be hyper-methylated in the three genes. By integrating with the oncogenes status, we demonstrated that EGFR wt and SRGN overexpressed patients were associated with chronic inflammation and immune evasion, showing an immunologically hot phenotype, which might lead to the short OS but derive clinical benefit from ICIs.ConclusionsThis study identifies hyper-methylation and concurrent repression of CD247, LCK, PSTPIP1 as immune negative indicators and risk factors for prognosis in LUAD. Moreover, EGFR/SRGN axis may participate in immune modification to influence ICIs response and clinical outcome in LUAD.

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Deubiquitinase UCHL5 is elevated and associated with a poor clinical outcome in lung adenocarcinoma (LUAD).

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