Systematic Analysis of the Aberrances and Functional Implications of UPR in Hepatocellular Carcinoma

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Abstract Background Unfolded protein response (UPR), an orchestrating adaptive mechanism activated by endoplasmic reticulum (ER) stress, plays an instrumental protumoral roles in several kinds of cancers, and high unfolded protein response is correlated to poorer prognosis and malignant hallmark. Considerable evidence indicates that UPR induced by oncogenic conditions is a distinguishing feature of cancer. Methods Bioinformatics mining was carried out by using the public pancer data of TCGA and other public databases to analyze the differential gene expression profiles of the patients and Cox regression analysis to find out the differentially expressed endoplasmic reticulum stress related genes with prognostic value. ER-stress Potential Index (EPI) was defined to computationally dissect the UPR trends via gene set enrichment analysis using R package ‘GSVA’. Combined with TCGA and GEO databases, the clinical characteristics of EPI were comprehensively analyzed in LIHC. Virtual screening was performed to find out potential compounds targeting STC2, which was a good diagnostic marker and pharmacological target towards endoplasmic reticulum stress in LIHC. Results Pan-cancer analysis results showed that unfolded protein response pathway was generally positive associated with poor prognosis of patients across different cancer types. It would be an important and ubiquitous mechanism in different tumors. High EPI was positive associated with tumor malignant phenotype, including higher death rate, recurrence rate, metastatic risk, larger tumor size and other undesirable aggressive clinical traits. In addition, EPI was also responsible for immune evasion via upregulating the expression of immunosuppressive gene and facilitating the production of pro-inflammatory and immunomodulatory cytokines. Besides, EPI played pivotal role in liver cancers’ resistance of chemotherapy and therapeutic targeting UPR would be enhance the anti-tumor effectiveness. STC2 would be a good diagnostic marker and pharmacological target in LIHC. Through virtual screening, we found that flavonoids compounds could be a good compound targeting STC2. Flavonoids could become a good pharmaceutical therapeutic candidate in unique or adjuvant therapeutic approaches toward LIHC. Conclusion EPI was associated with subtypes and clinical features and providing new insight into tumor biology and can guide efficient pharmalogical intervention of unfolded protein response to help patients.

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