Department of Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University, School of Medicine, Springfield, IL.
Int J Cancer. 2013 Nov 15;133(10):2307-14. doi: 10.1002/ijc.28270. Epub 2013 Jun 8.
We recently reported on the isolation and characterization of calcium sensing receptor (CaSR) null human colon cancer cells (Singh et al., Int J Cancer 2013; 132: 1996-2005). CaSR null cells possess a myriad of molecular features that are linked to a highly malignant and drug resistant phenotype of colon cancer. The CaSR null phenotype can be maintained in defined human embryonic stem cell culture medium. We now show that the CaSR null cells can be induced to differentiate in conventional culture medium, regained the expression of CaSR with a concurrent reversal of the cellular and molecular features associated with the null phenotype. These features include cellular morphology, expression of colon cancer stem cell markers, expression of survivin and thymidylate synthase and sensitivity to fluorouracil. Other features include the expression of epithelial mesenchymal transition linked molecules and transcription factors, oncogenic miRNAs and tumor suppressive molecule and miRNA. With the exception of cancer stem cell markers, the reversal of molecular features, upon the induction of CaSR expression, is directly linked to the expression and function of CaSR because blocking CaSR induction by shRNA circumvented such reversal. We further report that methylation and demethylation of the CaSR gene promoter underlie CaSR expression. Due to the malignant nature of the CaSR null cells, inclusion of the CaSR null phenotype in disease management may improve on the mortality of this disease. Because CaSR is a robust promoter of differentiation and mediates its action through diverse mechanisms and pathways, inactivation of CaSR may serve as a new paradigm in colon carcinogenesis.
我们最近报道了钙敏感受体 (CaSR) 缺失的人类结肠癌细胞的分离和鉴定（Singh 等人，Int J Cancer 2013；132:1996-2005）。CaSR 缺失细胞具有与结肠癌高度恶性和耐药表型相关的众多分子特征。CaSR 缺失表型可以在定义的人胚胎干细胞培养基中维持。我们现在表明，CaSR 缺失细胞可以在常规培养基中诱导分化，恢复 CaSR 的表达，同时逆转与缺失表型相关的细胞和分子特征。这些特征包括细胞形态、结肠癌干细胞标志物的表达、survivin 和胸苷酸合成酶的表达以及对氟尿嘧啶的敏感性。其他特征包括上皮间质转化相关分子和转录因子、致癌 miRNA 和肿瘤抑制分子和 miRNA 的表达。除了癌症干细胞标志物外，CaSR 表达诱导后分子特征的逆转与 CaSR 的表达和功能直接相关，因为通过 shRNA 阻断 CaSR 诱导可以避免这种逆转。我们进一步报告说，CaSR 基因启动子的甲基化和去甲基化是 CaSR 表达的基础。由于 CaSR 缺失细胞的恶性性质，将 CaSR 缺失表型纳入疾病管理可能会提高这种疾病的死亡率。由于 CaSR 是分化的强大启动子，并通过多种机制和途径介导其作用，因此 CaSR 的失活可能成为结肠癌发生的新范例。
