Molecular mechanism of hepatitis B virus (HBV) on suppression of raf kinase inhibitor protein (RKIP) expression

Abstract

Raf kinase inhibitor protein (RKIP) has been shown to be a suppressor of the mitogen-activated protein kinase pathway and is reported to be involved in human malignancy. However, the molecular mechanism of hepatitis B virus (HBV) in regulating RKIP expression is not yet clarified. In this study, we compared RKIP expression in 107 pairs of matched liver cancer and adjacent non-cancerous liver tissues. Among seven HBV-encoded proteins, we found HBV X (HBX) protein could significantly inhibit the expression level of RKIP, indicating that HBV could suppress RKIP expression through regulating HBX. To further elucidate the mechanism, analyses on transcriptional regulation and promoter methylation inhibition were conducted in Huh7 cells. Our results showed that HBX can interact with AP1 protein to inhibit the RKIP transcription. Moreover, we observed that the promoter methylation level of RKIP could be enhanced by HBV. In conclusion, our study revealed that RKIP could act as a molecular marker for HBV-infected liver cancer, but had no tumor-suppressing effect.

RKIP Regulates Differentiation-Related Features in Melanocytic Cells

“…Several studies have shown that RKIP exhibits low expression levels in various cancers and it is often absent in metastases [ 5 , 8 , 9 , 10 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. In agreement, decreased RKIP expression has been associated with metastatic uveal melanoma while low levels of RKIP were detected on both metastatic as well as non-metastatic cutaneous melanoma biopsies [ 15 , 49 ].…”

“…RKIP is a multifunctional protein involved in carcinogenesis regulating cellular growth, motility, epithelial to mesenchymal transition and invasion [ 51 , 52 , 53 ]. Several authors have suggested that RKIP may not have a significant role in primary tumors but that instead, this protein could play an important role as a metastatic suppressor [ 5 , 8 , 9 , 10 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. In this sense, and despite the described role for RKIP in the regulation of the MAPK/ERK pathway, RKIP has been implicated on the invasive behavior of malignant melanoma cells but not on their proliferative capability [ 14 ].…”

RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact

“…Several studies have shown that RKIP exhibits low expression levels in various cancers and it is often absent in metastasis [8,9,17,19,43,45,48,49,50,51,52,53,54,55,56,57,58,59,60]. RKIP loss has been suggested to result by hypermethylation of its promoter [41].…”

“…RKIP has been identified as an important protein in various cancer types, including those of prostate, melanoma, colorectal, liver, breast, urinary bladder, nasopharyngeal carcinoma, skin, lung and others [ 17 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. Several studies have shown that RKIP exhibits low expression levels in various cancers and it is often absent in metastasis [ 8 , 9 , 17 , 19 , 43 , 45 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. RKIP loss has been suggested to result by hypermethylation of its promoter [ 41 ].…”

Molecular Mechanisms and Animal Models of HBV-Related Hepatocellular Carcinoma: With Emphasis on Metastatic Tumor Antigen 1

“…For a complete list of the HBx interacting proteins, please refer to review papers [63,64]. HBx per se cannot bind directly to DNA; instead, HBx transactivates viral and cellular promoters through interacting with transcription factors, for example, MYC [65], cAMP response element-binding protein (CREB) [66], activating protein 1 (AP-1) [67], RNA polymerase binding protein [68], nuclear factor kappa B (NF-κB) [59], etc. HBx can also mediate epigenetic plasticity by interacting with histone acetyltransferase [69] and core components of methyltransferase complexes and, e.g., DNMT3a, DNMT3b, and WD Repeat Domain 5 Protein [70], etc.…”