Bhatelia Khyati, Singh Aru, Tomar Dhanendra, Singh Kritarth, Sripada Lakshmi, Chagtoo Megha, Prajapati Paresh, Singh Rochika, Godbole Madan M, Singh Rajesh
Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Gandhinagar, India.
Deptartment of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, UP, India.
Biochim Biophys Acta. 2014 Feb;1842(2):144-53. doi: 10.1016/j.bbadis.2013.11.006. Epub 2013 Nov 13.
Emerging evidences suggest that chronic inflammation is one of the major causes of tumorigenesis. The role of inflammation in regulation of breast cancer progression is not well established. Recently Mediator of IRF3 Activation (MITA) protein has been identified that regulates NF-κB and IFN pathways. Role of MITA in the context of inflammation and cancer progression has not been investigated. In the current report, we studied the role of MITA in the regulation of cross talk between cell death and inflammation in breast cancer cells. The expression of MITA was significantly lower on in estrogen receptor (ER) positive breast cancer cells than ER negative cells. Similarly, it was significantly down regulated in tumor tissue as compared to the normal tissue. The overexpression of MITA in MCF-7 and T47D decreases the cell proliferation and increases the cell death by activation of caspases. MITA positively regulates NF-κB transcription factor, which is essential for MITA induced cell death. The activation of NF-κB induces TNF-α production which further sensitizes MITA induced cell death by activation of death receptor pathway through capsase-8. MITA expression decreases the colony forming units and migration ability of MCF-7 cells. Thus, our finding suggests that MITA acts as a tumor suppressor which is down regulated during tumorigenesis providing survival advantage to tumor cell.
新出现的证据表明，慢性炎症是肿瘤发生的主要原因之一。炎症在乳腺癌进展调控中的作用尚未完全明确。最近发现了干扰素调节因子3激活介质（MITA）蛋白，它可调节核因子-κB（NF-κB）和干扰素途径。MITA在炎症和癌症进展中的作用尚未得到研究。在本报告中，我们研究了MITA在调节乳腺癌细胞死亡与炎症之间相互作用中的作用。雌激素受体（ER）阳性乳腺癌细胞中MITA的表达明显低于ER阴性细胞。同样，与正常组织相比，肿瘤组织中MITA的表达明显下调。在MCF-7和T47D细胞中过表达MITA可通过激活半胱天冬酶来降低细胞增殖并增加细胞死亡。MITA正向调节NF-κB转录因子，这对MITA诱导的细胞死亡至关重要。NF-κB的激活诱导肿瘤坏死因子-α（TNF-α）的产生，TNF-α通过激活半胱天冬酶-8死亡受体途径进一步使MITA诱导的细胞死亡敏感化。MITA的表达降低了MCF-7细胞的集落形成单位和迁移能力。因此，我们的研究结果表明，MITA作为一种肿瘤抑制因子，在肿瘤发生过程中被下调，从而为肿瘤细胞提供生存优势。
