Treatment with an SLC12A1 antagonist inhibits tumorigenesis in a subset of hepatocellular carcinomas

Abstract

A central aim in cancer research is to identify genes with altered expression patterns in tumor specimens and their potential role in tumorigenesis. Most types of tumors, including hepatocellular carcinoma (HCC), are heterogeneous in terms of genotype and phenotype. Thus, traditional analytical methods like the t-test fail to identify all oncogenes from expression profiles. In this study, we performed a meta-Cancer Outlier Profile Analysis (meta-COPA) across six microarray datasets for HCC from the GEO database. We found that gene SLC12A1 was overexpressed in the Hep3B cell line, compared with five other HCC cell lines and L02 cells. We also found that the upregulation of SLC12A1 was mediated by histone methylation within its promoter region, and that SLC12A1 is a positive regulator of the WNK1/ERK5 pathway. Consistent with in vitro results, treatment with the SLC12A1 antagonist Bumetanide delayed tumor formation and reduced Hep3B cell tumor size in mouse xenografts. In summary, our research reveals a novel subset of HCCs that are sensitive to SLC12A1 antagonist treatment, thereby offering a new strategy for precision HCC treatment.

Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma

“…The expression of α-SMA and Col4a3 mRNA was higher in the tumorous than non-tumorous tissues of all mice, regardless of chemerin-156 overexpression (Figure 4a,b). Consistent with previous reports [32][33][34][35], early growth response gene-1 (Egr-1), solute carrier family 12 member 1 (Slc12a1), and serine peptidase inhibitor, Kazal type 1 (Spink1) mRNA levels were higher in tumorous than non-tumorous tissues, whereas glucose-6-phosphatase (G6PC) was reduced (Figure 4c-f). However, this effect was similar regardless of chemerin-156 overexpression.…”

Clinical significance of long non-coding RNA DUXAP8 and its protein coding genes in hepatocellular carcinoma

“…A previous study showed that bumetanide, a SLC12A1 antagonist, inhibited cell proliferation, tumorigenesis, and metastasis in HCC cell lines (59). The study also suggested that bumetanide slows down tumor growth by interfering with the cell cycle rather than by inducing cytotoxicity (59). Studies testing the ability of bumetanide to enhance tumor necrosis in a rat model of N1-S1 HCC.…”

SLC12A8 plays a key role in bladder cancer progression and EMT

“…Reports about the specific function of SLC12A8 on cancer cells or normal cells proliferation and EMT were limited. Via reviewing the published articles, we observed that SLC12A1, a member of SLC12A family, was a positive regulator of WNK/ERK5 pathway, which can promote cell proliferation and survival [ 11 ]. Moreover, suppressing SLC12A1 might inhibit proliferation-related genes like Cyclin D1, a key proliferation checkpoint [ 36 ].…”

“…The family has two major branches: one is a sodium-dependent cotransporter, including SLC12A2, SLC12A1, and SLC12A3, and the second is a potassium and chloride cotransporter containing four members (SLC12A4, SLC12A5, SLC12A6, and SLC12A7); besides, there are also two other members, SLC12A8 and SLC12A9, whose functions have not been revealed [ 8 , 9 ]. From the current researches on SLC12 family, we learned that the expression of SLC12A1 is associated with glioma and hepatocellular carcinomas [ 10 , 11 ]. Moreover, it has been reported that the overexpression of SLC12A5 promoted the development and metastasis of tumor and is highly related to the significant decrease in patients’ survival with colorectal carcinoma and ovarian carcinoma [ 12 , 13 ].…”