Effect of SLC5A8 Missense Variants on Its Tumor-Suppressive Function.

IF 2.3 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
Seung Yeon Ha, Hyo Sook Song, Jin-Young Kim, Youn-Hee Choi, Ji Ha Choi
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引用次数: 0

Abstract

Background: Solute carrier family-5 member-8 (SLC5A8) serves as a plasma membrane transporter for monocarboxylates, such as lactate, butyrate, pyruvate, acetate, propionate, nicotinate, and β-hydroxybutyrate. SLC5A8 can suppress colorectal cancer (CRC), and its tumor-suppressive function is mainly associated with butyrate, propionate, and pyruvate, which inhibit histone deacetylase. Although SLC5A8 is an important tumor suppressor, the impact of SLC5A8 variants on its tumor-suppressive function have not been reported. In this study, we investigated the effects of SLC5A8 missense variants on the expression and tumor-suppressive function of the transporter using various in vitro assays.

Methods: Common SLC5A8 missense variations were identified using data from the Database of Single-Nucleotide Polymorphisms of the National Center for Biotechnology Information. We generated HCT116 and DLD-1 cell lines stably overexpressing wild-type SLC5A8 or SLC5A8 variants. The effect of each variant on SLC5A8 expression was examined via immunoblotting. Finally, using colony-formation, wound-healing, and invasion assays, we investigated whether the decrease in SLC5A8 expression resulting from its variants could affect the tumor-suppressive function of the transporter.

Results: We identified two common missense single-nucleotide polymorphisms of SLC5A8, Val193Ile (rs1709189) and Met490Ile (rs164365), and assembled two major haplotypes of SLC5A8. Among these haplotypes, haplotype 1 contained wild-type SLC5A8 mRNA sequences and H2 contained two variants: Val193Ile and Met490Ile. Val193Ile and H2 significantly decreased SLC5A8 expression. These variants significantly increased the proliferation, migration, and invasion abilities of CRC cells.

Conclusion: Decreased SLC5A8 expression caused by missense SLC5A8 variants appeared to significant impair the tumor-suppressive function of the transporter.

SLC5A8错义变异对其肿瘤抑制功能的影响
背景:溶质载体家族5成员-8 (SLC5A8)作为单羧酸盐的质膜转运体,如乳酸盐、丁酸盐、丙酮酸盐、醋酸盐、丙酸盐、烟酸盐和β-羟基丁酸盐。SLC5A8具有抑制结直肠癌(CRC)的作用,其抑瘤功能主要与抑制组蛋白去乙酰化酶的丁酸盐、丙酸盐和丙酮酸盐有关。虽然SLC5A8是一种重要的肿瘤抑制因子,但SLC5A8变异对其肿瘤抑制功能的影响尚未见报道。在这项研究中,我们通过各种体外实验研究了SLC5A8错义变体对转运蛋白表达和肿瘤抑制功能的影响。方法:利用国家生物技术信息中心单核苷酸多态性数据库的数据,鉴定常见的SLC5A8错义变异。我们生成了稳定过表达SLC5A8或SLC5A8变体的HCT116和DLD-1细胞系。通过免疫印迹检测各变异对SLC5A8表达的影响。最后,通过集落形成、伤口愈合和侵袭实验,我们研究了SLC5A8基因变异导致的SLC5A8表达降低是否会影响该转运体的肿瘤抑制功能。结果:鉴定出SLC5A8基因的两个常见错核苷酸多态性:Val193Ile (rs1709189)和Met490Ile (rs164365),并组装出SLC5A8基因的两个主要单倍型。在这些单倍型中,单倍型1包含野生型SLC5A8 mRNA序列,H2包含两个变体:Val193Ile和Met490Ile。Val193Ile和H2显著降低SLC5A8的表达。这些变异显著增加了结直肠癌细胞的增殖、迁移和侵袭能力。结论:SLC5A8错义变异引起的SLC5A8表达下降明显损害了该转运体的肿瘤抑制功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Korean Medical Science
Journal of Korean Medical Science 医学-医学:内科
CiteScore
7.80
自引率
8.90%
发文量
320
审稿时长
3-6 weeks
期刊介绍: The Journal of Korean Medical Science (JKMS) is an international, peer-reviewed Open Access journal of medicine published weekly in English. The Journal’s publisher is the Korean Academy of Medical Sciences (KAMS), Korean Medical Association (KMA). JKMS aims to publish evidence-based, scientific research articles from various disciplines of the medical sciences. The Journal welcomes articles of general interest to medical researchers especially when they contain original information. Articles on the clinical evaluation of drugs and other therapies, epidemiologic studies of the general population, studies on pathogenic organisms and toxic materials, and the toxicities and adverse effects of therapeutics are welcome.
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