a Department of Gastroenterology , The Second Affiliated Hospital of Chongqing Medical University , Chongqing , China.
b Department of Pathology , the 309th hospital of PLA , Beijing , China.
Cell Cycle. 2019 Feb;18(4):511-522. doi: 10.1080/15384101.2019.1578145. Epub 2019 Feb 11.
The acidic extracellular microenvironment, namely acidosis, is a biochemical hallmark of solid tumors. However, the tumorigenicity, metastatic potential, gene expression profile and chromatin accessibility of acidosis-adapted colorectal cancer cells remain unknown. The colorectal cancer cell SW620 was cultured in acidic medium (pH 6.5) for more than 3 months to be acidosis-adapted (SW620-AA). In comparison to parental cells, SW620-AA cells exhibit enhanced tumorigenicity and liver metastatic potential in vivo. Following mRNA and lncRNA expression profiling, we validated that OLMF1, NFIB, SMAD9, DGKB are upregulated, while SESN2, MAP1B, UTRN, PCDH19, IL18, LMO2, CNKSR3, GXYLT2 are downregulated in SW620-AA cells. The differentially expressed mRNAs were significantly enriched in DNA remodeling-associated pathways including HDACs deacetylate histones, SIRT1 pathway, DNA methylation, DNA bending complex, and RNA polymerase 1 chain elongation. Finally, chromatin accessibility evaluation by ATAC-sequencing revealed that the differentially opened peaks were enriched in pathways such as small cell lung cancer, pathways in cancer, ErbB signaling, endometrial cancer, and chronic myeloid leukemia, which were mainly distributed in intergenic regions and introns. These results suggest that the chromatin accessibility changes are correlated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells.
酸性细胞外微环境，即酸中毒，是实体瘤的一个生化标志。然而，适应酸中毒的结直肠癌细胞的致瘤性、转移潜能、基因表达谱和染色质可及性仍然未知。将结直肠癌细胞 SW620 在酸性培养基（pH 6.5）中培养超过 3 个月以适应酸中毒（SW620-AA）。与亲本细胞相比，SW620-AA 细胞在体内表现出增强的致瘤性和肝转移潜能。在进行 mRNA 和 lncRNA 表达谱分析后，我们验证了 OLMF1、NFIB、SMAD9、DGKB 上调，而 SESN2、MAP1B、UTR、PCDH19、IL18、LMO2、CNKSR3、GXYLT2 在 SW620-AA 细胞中下调。差异表达的 mRNAs 显著富集在 DNA 重塑相关途径中，包括 HDACs 去乙酰化组蛋白、SIRT1 途径、DNA 甲基化、DNA 弯曲复合物和 RNA 聚合酶 1 链延伸。最后，通过 ATAC-seq 进行染色质可及性评估显示，差异开放峰富集在小细胞肺癌、癌症途径、ErbB 信号、子宫内膜癌和慢性髓性白血病等途径中，主要分布在基因间区域和内含子中。这些结果表明，染色质可及性的变化与适应酸中毒的结直肠癌细胞生长和肝转移能力的增强有关。
