Upregulation of Cystathionine-β-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis.
Upregulation of Cystathionine-β-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis.
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DOI：
10.1158/0008-5472.can-16-3480
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发表时间：
2017-11-01
期刊：
影响因子：
11.2
通讯作者：
Hellmich MR
中科院分区：
文献类型：
--
作者：
Phillips CM;Zatarain JR;Nicholls ME;Porter C;Widen SG;Thanki K;Johnson P;Jawad MU;Moyer MP;Randall JW;Hellmich JL;Maskey M;Qiu S;Wood TG;Druzhyna N;Szczesny B;Módis K;Szabo C;Chao C;Hellmich MR
转硫酶胱硫醚-β-合酶（CBS）及其产物硫化氢（H2S）在结直肠癌中异常上调，其中它们通过自分泌和旁分泌机制促进肿瘤生长和进展。然而，CBS/H2S轴是否在结直肠癌发生中起作用尚不清楚。在这里，我们报告了CBS在人类癌前腺瘤性息肉活检组织中的上调，并表明CBS在腺瘤样结肠上皮细胞系中的强制上调足以诱导结直肠癌细胞的代谢和基因表达特征。差异表达的代谢产物（65种增加，20种减少）聚集在糖酵解途径、核苷酸糖、戊糖磷酸途径的中间产物和脂肪生成中，主要包括磷脂、鞘脂和胆汁酸。CBS上调诱导了NCM 356细胞转录组的广泛变化，具有超过350个差异表达的基因。这些基因与糖酵解、缺氧和结肠癌细胞表型相关的基因组显著重叠，包括受NF-κB、KRAS、p53和Wnt信号调节的基因，E-钙粘蛋白敲低后下调的基因，以及与细胞外基质增加、细胞粘附和上皮-间质转化相关的基因。CBS诱导的合成代谢转换与免疫受损小鼠中增加的NCM 356细胞生物能量学、增殖、通过基质胶的侵袭、抗失巢凋亡和CBS依赖性肿瘤发生相关。CBS杂合子小鼠（CBS+/−）中CBS的基因消融减少了诱变剂诱导的异常结肠隐窝病灶的数量。总之，这些结果证实CBS/H2S轴的活化促进结肠癌发生。
The transsulfuration enzyme cystathionine-β-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differentially expressed metabolites (65 increased and 20 decreased) clustered into the glycolytic pathway, nucleotide sugars, intermediates of the pentose phosphate pathway, and lipogenesis, including primarily phospholipids, sphingolipids, and bile acids. CBS upregulation induced broad changes in the NCM356 cell transcriptome with over 350 differentially expressed genes. These genes overlapped significantly with gene sets related to glycolysis, hypoxia, and a colon cancer cell phenotype, including genes regulated by NF-κB, KRAS, p53, and Wnt signaling, genes downregulated after E-cadherin knockdown, and genes related to increased extracellular matrix, cell adhesion, and epithelial-to-mesenchymal transition. The CBS-induced switch to an anabolic metabolism was associated with increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immune compromised mice. Genetic ablation of CBS in CBS heterozygous mice (CBS+/−) reduced the number of mutagen-induced aberrant colonic crypt foci. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis.