Identification of biomarkers based on ubiquitin-correlated genes for predicting immune profile and drug sensitivity in lung adenocarcinoma

Yue Li¹Wei Tian²Chen Chen¹Hailin Liu¹Zhenfa Zhang¹Changli Wang^1*

• ¹Department of Lung Cancer, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin, China
• ²Department of General Surgery, the second affiliated hospital of tianjin university of traditional chinese medicine, Tianjin, China

Background: Lung adenocarcinoma (LUAD) shows high recurrence rate and poor prognosis. Genes associated with ubiquitin play a role in the onset and advancement of cancers; however, they have yet to be employed for the diagnosis and prognosis of LUAD.Methods: First, gene modules correlated with ubiquitin were identified by WGCNA.The expression profiles obtained were intersected with differential genes taken between the LUAD and control samples. The genes were then further compressed using one-way and multifactorial Cox regression analyses and risk models. In addition, the model was validated by constructing a nomogram using clinical characteristics and Riskscore. Next, the differences in immune infiltration between different subgroups were explored, and immunotherapy and drug sensitivity evaluations were Therefore, new prognostic markers are urgently needed to assess patients' prognosis and guide treatment decisions.performed. The biological role of HEATR1 in LUAD was also explored using CCK-8, wound healing assay and transwell.Results: The intersection between the module genes between LUAD samples and control samples and differentially expressed genes (DEGs) yielded 197 intersected genes after we screened three particular modules with the strongest ubiquitin association by WGCNA. And 32 genes associated with LUAD prognosis were screened, and B4GALT4, DNAJB4, GORAB, HEATR1, LPGAT1, FAT1, GAB2, MTMR4 and TCP11L2 were selected as independent prognosis genes for risk modeling. Patients were classified into low-and high-risk groups by the Riskscore.Low-risk patients had markedly better overall survival (OS) than those in the high-risk group. The quantity of immune cell infiltration between the two patient groups varied notably, and the expression of model genes was negatively connected with the infiltration of the great majority of immune cells. The medications TAE684, Cisplatin, and Midostaurin exhibited the largest negative connection with Riskscore, according to drug sensitivity study. Lastly, we demonstrated through in vitro tests that HEATR1 knockdown markedly reduced LUAD cell survival, migration, and invasion.This study is the first to systematically integrate the ubiquitin pathway with multi-omics data, constructing a robust risk model for LUAD prognosis and immune characteristics, providing a theoretical reference for future exploration of potential biomarkers for LUAD patient diagnosis.