Serum deprivation-response protein induces apoptosis in hepatocellular carcinoma through ASK1-JNK/p38 MAPK pathways

Xi Chen,Zhisu Liu,Qi Zhang,Jinghua Li,Weijie Ma,Yingyi Liu,Kunlei Wang,Yonghua Guo,Xiaoling Wu,Yufeng Yuan,Chengjie Mei,Xiang Jiang,Ye Yao,Yiran Chen,Ganggang Wang

doi:10.1038/s41419-021-03711-x

Abstract

Serum deprivation-response protein (SDPR), a phosphatidylserine-binding protein, which is known to have a promising role in caveolar biogenesis and morphology. However, its function in hepatocellular carcinoma (HCC) was still largely unknown. In this study, we discussed the characterization and identification of SDPR, and to present it as a novel apoptosis candidate in the incidence of HCC. We identified 81 HCC cases with lower SDPR expression in the tumor tissues with the help of qRT-PCR assay, and lower SDPR expression was potentially associated with poor prognostication. The phenotypic assays revealed that cell proliferation, invasion, and migration were profoundly connected with SDPR, both in vivo and in vitro. The data obtained from the gene set enrichment analysis (GSEA) carried out on the liver hepatocellular carcinoma (LIHC), and also The Cancer Genome Atlas (TCGA) findings indicated that SDPR was involved in apoptosis and flow cytometry experiments further confirmed this. Furthermore, we identified the interaction between SDPR and apoptosis signal-regulating kinase 1 (ASK1), which facilitated the ASK1 N-terminus-mediated dimerization and increased ASK1-mediated signaling, thereby activating the JNK/p38 mitogen-activated protein kinases (MAPKs) and finally enhanced cell apoptosis. Overall, this work identified SDPR as a tumor suppressor, because it promoted apoptosis by activating ASK1-JNK/p38 MAPK pathways in HCC.

Highlights

Hepatocellular carcinoma (HCC) has been identified as the most common type of primary liver cancers, the latest epidemiological studies showed that HCC accounted for the third largest number of tumor-related deaths
serum deprivation-response protein (SDPR) was significantly downregulated in HCC and was associated with HCC prognosis To identify the function of SDPR, the SDPR expression profile was accessed by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR)
The results revealed a considerably lower expression of SDPR mRNA in HCC tissues compared to peritumor tissues (Fig. 1A)

Summary

Introduction

Hepatocellular carcinoma (HCC) has been identified as the most common type of primary liver cancers, the latest epidemiological studies showed that HCC accounted for the third largest number of tumor-related deaths. We reported a novel tumor suppressor, serum deprivation-response protein (SDPR) ( called cavin-2), in inducing HCC cell apoptosis. SDPR was firstly identified as a phosphatidylserine-binding protein, as a member of cavin family, SDPR has been studied on the role of regulating caveolae formation and inducing membrane curvature[8], but the potential function in cancer was rarely described previously. Evidence from a recent study showed that SDPR was a metastasis suppressor through inhibiting epithelial–mesenchymal transition (EMT), migration and promoting apoptosis by relieving the inhibition of the extracellular-signal-regulated kinase (ERK) pathway in breast tumor[9]. Its specific functions and mechanisms in HCC still remains undiscovered

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Results

Conclusion