Integrative Analysis Reveals the Potential Role and Prognostic Value of GOLM1 in Hepatocellular Carcinoma

Abstract

Overexpression of Golgi membrane protein 1 (GOLM1) is closely associated with hepatocellular carcinoma (HCC) vascular invasion. How GOLM1 may be involved in angiogenesis in HCC remains unclear. We explored how GOLM1 promotes angiogenesis in HCC and potential prognostic value. Expression levels of GOLM1 in HCC patients and healthy controls were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) between HCC patients and controls were compared. GOLM1 was knocked out in the HCC cell line, and RNA sequencing and DEG expression analysis were performed compared with control cells. Based on TCGA data and cell line RNA sequencing data, DEGs affected by a high expression of GOLM1 were identified. Subsequently, enrichment analysis was performed to explore the functions and pathways of the DEGs affected by a high expression of GOLM1. A relevant network analysis was built. Cox regression, genomic variance analysis scores, minimum absolute shrinkage and selection operator regression, and random forest regression models were applied to determine the best prognostic model and validated using the GSE54236 dataset from the Gene Expression Omnibus (GEO). We determined the effect of GOLM1 expression on immune cell infiltration in liver cancer. GOLM1 was overexpressed in HCC tissues compared with controls, and its level correlated with tumor purity and prognosis. 400 DEGs affected by highly expressed GOLM1 were identified in TCGA and cell line RNA sequencing data. Enrichment analysis revealed that these DEGs may be related to biological processes of oxidative stress and angiogenesis and involved in the VEGF signaling pathway and protein processing in endoplasmic reticulum. We predicted a comprehensive regulatory network in which GOLM1 activated VEGF signaling to promote HCC angiogenesis. GOLM1 may interact with E2F1 and IGF2BP3 to promote angiogenesis. GOLM1 overexpression was associated with greater immune cell infiltration. A random forest regression model was the best prognostic model. Our study reveals a potential molecular mechanism of GOLM1 in promoting HCC. We developed two prognostic models based on DEG associated with GOLM1 overexpression to help stratify HCC prognosis and improve individualized treatment.

Unveiling the impact of GOLM1/GP73 on cytokine production in cancer and infectious disease

“…Indeed, overexpression of GOLM1 leads to increased signaling of JAK and STAT3 in the lung adenocarcinoma cell line A549, 46 possibly due to alterations in autocrine cytokine signaling. All these mechanisms likely contribute to the effects of GOLM1 on gene expression, 29 including downregulation of IFNB, 33,36 IL12A, 33,38 and upregulation of CXCL10 33 and CCL2. 43 However, at least part of the different effects of GOLM1 on cytokine and chemokine production might be caused by differences between full-length GOLM1 and the secreted form sGOLM1.…”

“…42 The higher expression of GOLM1 is associated with decreased survival in lung cancer, melanoma, colorectal cancer, uveal melanoma and HCC. 29,40,43,44 As recently reviewed elsewhere, 9 GOLM1 expression can be increased by multiple extracellular factors in the tumor microenvironment, including hypoxia, 22 various miRNAs, [45][46][47] and the cytokines IL-1b, 48 IL-6 and Oncostatin M. 49 However, the upregulation of GOLM1 is not a universal phenomenon in cancer, because lower levels of GOLM1 have been reported in colon cancer. 23 Likely as a consequence of aberrantly high expression of GOLM1, cancer cells can secrete high levels of sGOLM1, as reported for HCC 18,50 and prostate cancer.…”

“…23 Finally, molecular docking studies suggested that GOLM1 might interact with PTBP1 and E2F4, both involved in vascular epithelial growth factor (VEGF) signaling, but these interactions also need experimental confirmation. 29 The function of GOLM1 has not been clearly defined. Transgenic mice expressing a truncated form of GOLM1 lacking 146 residues of the C-terminus display a shortened lifespan.…”

“…23 Transcriptomics in the HCC cell line MHCC97H with knockdown and overexpression of GOLM1 revealed that GOLM1 influences genes associated with oxidative stress, angiogenesis and the VEGF signaling pathway. 29 Likely as a consequence of these GOLM1-associated cellular phenotypes, GOLM1 knockout mice had a higher susceptibility to mucosal inflammation, colitis induced epithelial damage and colon cancer. 23 Accordingly, the mRNA levels of the inflammatory cytokines IL-1b, IL-6, CCL2 and TNF were increased upon DSS (dextran sulfate sodium)-induced colitis.…”

“…As HCV infections increase GOLM1 expression 36,37 and can cause HCC, it is no surprise that GOLM1 expression levels are increased in HCC. 29,37 However, GOLM1 protein and mRNA levels are also increased in other, non-virally induced cancer types, for example lung cancer, prostate cancer, gastric cancer, melanoma, breast cancer and testicular cancer. 9,10,20,38,40,41 Elevated GOLM1 levels have also been reported in other liver pathologies, specifically non-alcoholic steatohepatitis and alcoholic liver disease.…”