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Background The protein high-mobility group AT-hook 1 (HMGA1) has been demonstrated that modulated cellular proliferation, invasion, and apoptosis with a poor prognosis in miscellaneous carcinomas. However, the mechanism of circumstantial carcinogenesis and association with the immune microenvironment of HMGA1 in hepatocellular carcinoma (HCC) had not been extensively explored. Methods The gene expression, clinicopathological correlation, and prognosis analysis were performed in the data obtained from TCGA. The results were further validated by ICGC and GEO database and external validation cohort from Guangxi. The HMGA1 protein expression was further examined in the HPA database. Biological function analyses were conducted by GSEA, STRING database, and Coexpedia online tool. Using TIMER and CIBERSORT method, the relationship between immune infiltrate and HMGA1 was investigated. Results In HCC, HMGA1 had much higher transcriptional and proteomic expression than in corresponding paraneoplastic tissue. Patients with high HMGA1 expression had a poor prognosis and unpromising clinicopathological features. High HMGA1 expression was closely related to the cell cycle, tumorigenesis, substance metabolism, and immune processes by regulating complex signaling pathways. Notably, HMGA1 may be associated with TP53 mutational carcinogenesis. Moreover, increased HMGA1 expression may lead to an increase in immune infiltration and a decrease in tumor purity in HCC. CIBERSORT analysis elucidated that the amount of B cell naive, B cell memory, T cells gamma delta, macrophages M2, and mast cell resting decreased when HMGA1 expression was high, whereas T cells follicular helper, macrophages M0, and Dendritic cells resting increased. Conclusion In conclusions, HMGA1 is a potent prognostic biomarker and a sign of immune infiltration in HCC, which may be a potential immunotherapy target for HCC.

Object: A large number of studies have suggested that stemness is an essential mechanism for drug resistance, metastasis and relapse in hepatocellular carcinoma (HCC). The aim of this study was to determine the impact of MCM2 on stemness and identify potential mechanisms that complement the stemness regulatory network in HCC. Methods: MCM2 expression features and prognostic significance were analyzed in multiple cohorts, including TCGA LIHC dataset, GSE14520 dataset, Guangxi cohort, and GSE76427 dataset. Stemness-related molecules and phenotypes were examined to evaluate the impact of MCM2 on stemness. The expression levels of key molecules of the hippo signaling pathway together with downstream target genes were examined to evaluate the effect of MCM2 on hippo signaling. This was further demonstrated by rescue experiments with hippo signaling pathway inhibitors (super-TDU). Sorafenib-resistant cells were constructed to assess the effect of MCM2 on drug resistance. A xenotransplantation model of nude mice was constructed to validate the role of MCM2 in vivo. Results: MCM2, which is expressed at higher levels in HCC tissue than in normal liver tissues, is a good indicator for distinguishing tumor tissues from normal liver tissues and can help differentiate HCC patients at different BCLC stages. The annotation of the differentially expressed genes in the MCM2 high and low expression groups indicated that MCM2 may be associated with the hippo signaling pathway. In addition, the expression of MCM2 in HCC tissues was correlated with the expression of YAP1/TAZ, which are key molecules of the hippo signaling pathway. It indicated that manipulation of MCM2 expression affects hippo signaling and stemness, while the inhibition of hippo signaling significantly reversed the effect of MCM2 on stemness. Disruption of MCM2 expression significantly elevated the sensitivity of sorafenib-resistant cells to sorafenib, as evidenced by the decrease in IC50 and diminished sphere-forming capacity. The in vivo assays showed that MCM2 effectively enhanced the efficacy of sorafenib. Conclusion: MCM2 is a good prognostic marker. MCM2 enhances the stemness of HCC cells by affecting the Hippo signaling pathway, while the downregulation of MCM2 inhibits resistance towards sorafenib.