Stemness-hypoxia genes , , and are associated with prognosis and tumor immune microenvironment in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The stemness of cancer cells and hypoxic microenvironment in HCC influence tumor progression and resistance to anti-tumor therapies. Herein, we aimed to combine tumoral stemness and hypoxia features to evaluate the prognosis and tumor immune microenvironment (TIME) in HCC.

Methods: Based on the HCC data from The Cancer Genome Atlas (TCGA) database, the mRNA expression-based stemness index (mRNAsi) was calculated, followed by acquisition of stemness-hypoxia genes. The prognostic stemness-hypoxia genes were identified using Cox regression analysis and a stemness-hypoxia prognostic model was constructed. The prognostic capacity of the model was validated, and the associations between the model and immune characteristics were evaluated. Moreover, the differential expression of model genes in HCC cells under hypoxia condition was determined.

Results: A three-gene prognostic signature based on the stemness-hypoxia genes (, , and ) was constructed. The Kaplan-Meier curve validated the prognostic capacity of the model. and were independent prognostic factors for HCC: expression was significantly associated with favorable overall survival (OS) of HCC patients, while expression was related to poor OS. Furthermore, the high-risk group was associated with advanced stages, infiltrated tumor-promoting immune cells, and elevated expression of immune checkpoints. The risk score also exhibited prognostic capacity for the OS and predictive value for the immune microenvironment in HCC. Finally, was significantly up-regulated in HepG2 cells compared to LO-2 cells. Additionally, elevated expression and reduced and expression were observed in both Hep3B and HepG2 cells under hypoxia condition.

Conclusions: Our established stemness-hypoxia gene signature showed favorable prognosis performance for HCC and was related to TIME. Our findings provide novel insights into the prognostic evaluation of HCC.