Carbohydrate Sulfotransferase 4 Inhibits the Progression of Hepatitis B Virus-Related Hepatocellular Carcinoma and Is a Potential Prognostic Marker in Several Tumors

Abstract

Carbohydrate sulfotransferase 4 (CHST4) plays an important role in lymphocyte homing and is abnormally expressed in several cancer types; however, its precise function in tumor development and progression is unknown. Here we confirm that CHST4 is aberrantly expressed in various tumor subtypes. In particular, we found that CHST4 expression was downregulated in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) tumors compared to paired normal tissue. We also showed that CHST4 overexpression inhibited the proliferation and metastasis of HCC cells in vitro. Clinically, CHST4 was identified as an independent prognostic factor for HBV-HCC patients. We further illuminated the anti-tumor role and mechanism of CHST4 in HBV-HCC by constructing a FENDRR-miR-10b-5p-CHST4 competing endogenous RNA network. We found that downregulation of CHST4 expression may promote HBV expression and regulate ribonucleoprotein complex biogenesis to promote malignant behaviors in HBV-HCC. CHST4 may also recruit CD4+ T cells, macrophages, dendritic cells, and neutrophils into the tumor microenvironment to inhibit the progression of HBV-HCC. Overall, our findings suggest that CHST4 acts as a tumor suppressor in HCC-HBV and represents a potential diagnostic and therapeutic target.

Multiomics Study of Key Differentially Expressed Methylation Genes in HCC Based on Epigenome and Transcriptome Analyses

“…The mutation and high expression of CHST4 were also found in gastric cancer tissues and gliomas, suggesting a poor prognosis [24,25]. In HCC, low mRNA expression and high protein expression of the CHST4 gene have been detected compared with normal tissues in previous studies [20]. Notably, higher CHST4 expression in HCC patients indicated poor overall survival (OS) and disease-free survival (DFS), which is consistent with our ndings, whereas lower CHST4 expression in HBV-induced HCC patients indicated poor OS and DFS.…”

“…Among all tumors, cholangiocarcinoma has the highest frequency of CHST4 gene change [20]. In colorectal adenocarcinoma, the transcriptional expression of the CHST4 gene was signi cantly higher than that in normal tissue [20]. Accelerated leukocyte in ltration occurred in CHST4 knockout mice, thus con rming the barrier protective role of CHST4 in colonic mucosa [23].…”

“…The expression and function of CHST4 in tumor cells have also been found and con rmed in previous studies. Among all tumors, cholangiocarcinoma has the highest frequency of CHST4 gene change [20]. In colorectal adenocarcinoma, the transcriptional expression of the CHST4 gene was signi cantly higher than that in normal tissue [20].…”

“…HEV is a special type of postcapillary venule characterized by lymphocyte homing. In normal human tissues, CHST4 expression can be detected in the intestinal tract, pancreas, and liver [20]. When in ammation is present, HEV-like blood vessels and GLCNA6ST-2 expression will appear at the source, such as the lungs of asthmatic sheep and the synovium of patients with rheumatoid arthritis [21,22].…”

“…These trends may be the result of low CHST4 expression promoting HBV expression and replication in liver cells in the absence of immune system defense [26]. Moreover, CHST4 overexpression has been proven to impede the migration ability of HCC cells [20].…”