Abstract
BackgroundThe HSP70 family of heat shock protein plays a critical role in protein synthesis and transport to maintain protein homeostasis. Several studies have indicated that HSP70s are related to the development and occurrence of various cancers.MethodsThe relationship between the overall survival rate of hepatocellular carcinoma patients and the expression of 14 HSP70s from multiple databases, such as TCGA, ONCOMINE, cBioPortal was investigated. Western Blot and PCR were used to evaluate HSPA4 and HSPA14 expressions in various HCC cells to identify suitable cell lines for further experiments .Wound-healing assays, Transwell assays and EdU assays were used to verify the effects of HSPA4 and HSPA14 on the function of hepatocellular carcinoma cells, and statistical analysis was performed.ResultsHepatocellular carcinoma tissues significantly expressed the 14 HSP70s compared to the normal samples. Besides, the high HSPA1A, HSPA1B, HSPA4, HSPA5, HSPA8, HSPA13, and HSPA14 expressions were inversely associated with the overall survival rate of patients, tumor grade, and cancer stage. A PPI regulatory network was constructed using the 14 HSP70s proteins with HSPA5 and HSPA8 at the network center. Univariate and multivariate analyses showed that HSPA4 and HSPA14 could be independent risk factors for the prognosis of hepatocellular carcinoma patients. Cell experiments have also confirmed that reducing HSPA4 and HSPA14 expressions can inhibit the invasion, metastasis, and proliferation of hepatocellular carcinoma cells.ConclusionsTherefore, the HSP70s significantly influence the occurrence and development of hepatocellular carcinoma. For instance, HSPA4 and HSPA14 can be novel therapeutic targets and prognostic biomarkers for hepatocellular carcinoma.
Highlights
Hepatocellular carcinoma (HCC) is a common and deadly cancer
HSP70 expressions in the HCC and normal tissues ONCOMINE and The Cancer Genome Atlas (TCGA) databases were used to analyze the mRNA expression of HSP70s to explore the different prognosis and potential therapeutic value of HSP70s in HCC patients
Roessler Liver 2 dataset showed significant HSPA4/13/14 overexpression in HCC tissues compared with the normal tissues with multiple changes of 2.202 times (p = 1.9E−72), 2.119 times (p = 9.4E−49), and 2.099 times (p = 7.76E−58), respectively
Summary
Hepatocellular carcinoma (HCC) is a common and deadly cancer. About 800,000 new cases and over 700,000 HCC-associated deaths are reported yearly [1]. Tumor cells depend on the maintenance of protein homeostasis via the molecular chaperones. HSP70s are ubiquitous molecular chaperones essential for folding and remodeling of all cellular proteins. Cancer cells can release HSP70s, which influence malignant characteristics via receptor-mediated signal transduction [4]. HSP70s can influence HCC occurrence and development via several mechanisms. Some studies have revealed that the HSP70 expression is upregulated in some human malignant tumors, such as liver, breast, pancreatic, colorectal, and prostate cancers [5,6,7,8,9]. A comprehensive study of various HSP70s in HCC is needed to clarify the molecular mechanisms involved in HCC development, providing potential therapeutic targets and prognostic markers of HCC. Several studies have indicated that HSP70s are related to the development and occurrence of various cancers
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