1. Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, Hubei 442000, China.
2. The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, China.
3. Department of Critical Care Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang 318000, China.
4. Department of Gastroenterology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang 318000, China.
* Contributed equally.
Background: Host cell factor 1 (HCFC1) was reported associated with the progression of a variety of cancers. However, its role in the prognosis and immunological characteristics of hepatocellular carcinoma (HCC) patients has not been revealed.
Methods: The expression and prognostic value of HCFC1 in HCC were investigated from the Cancer Genome Atlas (TCGA) dataset and a cohort of 150 HCC patients. The associations between HCFC1 expression with somatic mutational signature, tumor mutational burden (TMB), and microsatellite instability (MSI) were investigated. Next, the correlation of HCFC1 expression with immune cell infiltration was investigated. In vitro, cytological experiments were conducted to verify the role of HCFC1 in HCC.
Results: HCFC1 mRNA and protein upregulated in HCC tissues and correlated to poor prognosis. Multivariate regression analysis based on a cohort of 150 HCC patients revealed that high HCFC1 protein expression was an independent risk factor for prognosis. Upregulation of HCFC1 expression was associated with TMB, MSI, and tumor purity. HCFC1 expression showed a significant positive association with B cell memory, T cell CD4 memory, macrophage M0, and a significant positive association with immune checkpoint-related gene expression in the tumor microenvironment. HCFC1 expression negatively correlated to ImmuneScore, EstimateScore, and StromalScore. The single-cell RNA sequencing analysis demonstrated that the malignant cells and immune cells (B cells, T cells, and macrophages) represented high HCFC1 expression in HCC tissues. Functional analysis revealed that HCFC1 was remarkably correlated with cell cycle signaling. HCFC1 knockdown inhibited the proliferation, migration, and invasion capacity while promoting the apoptosis of HCC cells. At the same time, the cell-cycle-related proteins such as Cyclin D1 (CCND1), Cyclin A2 (CCNA2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) were downregulated.
Conclusion: Upregulation of HCFC1 predicted undesirable prognosis of HCC patients and promoted tumor progression through inhibiting cell cycle arrest.
Keywords: Host cell factor 1, Hepatocellular carcinoma, Cell cycle, Proliferation, Immune infiltration.