A Risk Model Based on Sorafenib-Response Target Genes Predicts the Prognosis of Patients with HCC

Abstract

Sorafenib is used to treat digestive system tumors in patients who do not respond to or cannot tolerate surgery. However, the roles and inhibitory mechanisms of sorafenib against hepatocellular carcinoma (HCC) are unclear. Differentially expressed genes in tissues from responders and nonresponders to sorafenib were investigated using the HCC GSE109211 data set. Biological functions and mechanisms were studied using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. The expression levels of differential expressed target genes were identified in HCC tissues, using The Cancer Genome Atlas database, and their prognostic and diagnostic values were explored using survival and receiver operating characteristic curve analysis. A nomogram and risk model of sorafenib-response target genes enabled the evaluation of the prognosis of patients with HCC. The relationship between risk scores and levels of infiltrating immune cells was visualized via correlation analysis. We identified 1620 sorafenib-response target genes involved in the PPAR signaling pathway, antigen processing and presentation, and ferroptosis. SLC41A3, SEC61A1, LRP4, PPM1G, and HSP90AA1 were independent risk factors for a poor prognosis for patients with HCC and had diagnostic value. A risk model based on SLC41A3, SEC61A1, LRP4, PPM1G, and HSP90AA1 expression showed that patients with HCC in the high-risk group had a worse prognosis. Consensus-clustering analysis (performed with K set to 2) distinguished two clusters (the cluster 1 and cluster 2 groups). Patients in cluster 1 survived significantly longer than those in cluster 2. The risk score correlated with the levels of T cells, cytotoxic lymphocytes, CD8+ T cells, macrophages, memory B cells, follicular helper T cells, and other immune cells. The high risk based on the sorafenib-response targets SLC41A3, SEC61A1, LRP4, PPM1G, and HSP90AA1 represented the poor prognosis for patients with HCC and significantly correlated with the levels of immune infiltrating cells in HCC.

Identifying Hub Genes Associated with Neoadjuvant Chemotherapy Resistance in Breast Cancer and Potential Drug Repurposing for the Development of Precision Medicine

“…RPSA was also found to promote pancreatic cancer invasion and metastasis through the MAPK signaling pathway [ 68 ]. SEC61A1 was reported to play a role in colon and hepatocellular cancer progression [ 69 , 70 , 71 ]. Hsa_circ_0007841 transcripted by SEC61A1 was found to be involved in drug resistance in doxorubicin and bortezomib-treated multiple myeloma patients [ 72 , 73 ].…”

Roles of peroxisome proliferator‐activated receptors in hepatocellular carcinoma

“…The safety and effectiveness of combination therapy with capecitabine, pioglitazone and rofecoxib for advanced HCC are assessed in a phase II clinical study, and the disease control rate is 79% 109 . The inhibitory effects of sorafenib on HCC may be associated with the PPAR signalling pathway 120 . Simvastatin has been shown to suppress hypoxia‐inducible factor‐1α/PPARγ/pyruvate kinase type M2‐mediated glycolysis to re‐sensitize HCC cells to sorafenib 110 .…”

“… 109 The inhibitory effects of sorafenib on HCC may be associated with the PPAR signalling pathway. 120 Simvastatin has been shown to suppress hypoxia‐inducible factor‐1α/PPARγ/pyruvate kinase type M2‐mediated glycolysis to re‐sensitize HCC cells to sorafenib. 110 PPARγ agonist rosiglitazone inhibits HCC migration by directly binding PPAR to the heparanase promoter, reducing heparanase gene transcription in HCC.…”