Elevated expression of LIF predicts a poor prognosis and promotes cell migration and invasion of clear cell renal cell carcinoma

Abstract

BackgroundRenal cell carcinoma (RCC) is the seventh most common cancer in humans, of which clear cell renal cell carcinoma (ccRCC) accounts for the majority. Recently, although there have been significant breakthroughs in the treatment of ccRCC, the prognosis of targeted therapy is still poor. Leukemia inhibitory factor (LIF) is a pleiotropic protein, which is overexpressed in many cancers and plays a carcinogenic role. In this study, we explored the expression and potential role of LIF in ccRCC.MethodsThe expression levels and prognostic effects of the LIF gene in ccRCC were detected using TCGA, GEO, ICGC, and ArrayExpress databases. The function of LIF in ccRCC was investigated using a series of cell function approaches. LIF-related genes were identified by weighted gene correlation network analysis (WGCNA). GO and KEGG analyses were performed subsequently. Cox univariate and LASSO analyses were used to develop risk signatures based on LIF-related genes, and the prognostic model was validated in the ICGC and E-MTAB-1980 databases. Then, a nomogram model was constructed for survival prediction and validation of ccRCC patients. To further explore the drug sensitivity between LIF-related genes, we also conducted a drug sensitivity analysis based on the GDSC database.ResultsThe mRNA and protein expression levels of LIF were significantly increased in ccRCC patients. In addition, a high expression of LIF has a poor prognostic effect in ccRCC patients. LIF knockdown can inhibit the migration and invasion of ccRCC cells. By using WGCNA, 97 LIF-related genes in ccRCC were identified. Next, a prognostic risk prediction model including eight LIF-related genes (TOB2, MEPCE, LIF, RGS2, RND3, KLF6, RRP12, and SOCS3) was developed and validated. Survival analysis and ROC curve analysis indicated that the eight LIF-related-gene predictive model had good performance in evaluating patients’ prognosis in different subgroups of ccRCC.ConclusionOur study revealed that LIF plays a carcinogenic role in ccRCC. In addition, we firstly integrated multiple LIF-related genes to set up a risk-predictive model. The model could accurately predict the prognosis of ccRCC, which offers clinical implications for risk stratification, drug screening, and therapeutic decision.

Identification and Validation of UPF1 as a Novel Prognostic Biomarker in Renal Clear Cell Carcinoma

“…The expression values were processed and normalized using the published protocols [ 21 ]. The expression levels of mRNA UPF1 were examined in TCGA and GEO cohorts, and divided into two groups based on the median expression: the high UPF1 expression group and the low UPF1 expression group.…”

Towards inmunotherapeutic exploitation strategies of rotumor and antitumor cytokines

“…IL-6 and LIF are two members of the IL-6 family that are involved not only in regenerative and inflammatory activities but also in a whole variety of pathological processes. Expression of both cytokines has been associated with poor prognosis in different cancer types (193)(194)(195)(196). In the tumor microenvironment (TME), IL-6 and LIF are mainly produced by epithelial and myeloid cells.…”

“…LIF plays essential roles in reproduction, such as blastocyst implantation and development and regulation of endometrial receptivity (198). Dysregulation of the LIF pathway is directly involved in the progression of tumors of different tissue lineages (199) such as renal (194), gastric (200), endometrial (201) and pancreatic cancers (196,202) among others. Importantly, LIF circulating levels predict poor outcomes in response to ICIs (203).…”