Chaudhary S, Madhukrishna B, Adhya A K, Keshari S, Mishra S K
Cancer Biology Laboratory, Gene Function and Regulation group, Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, Odisha, India.
Department of Pathology, Kalinga Institute of Medical Sciences, KIIT Rd, Chandaka Industrial Estate, Patia, Bhubaneshwar, Odisha, India.
Oncogenesis. 2016 Apr 18;5(4):e219. doi: 10.1038/oncsis.2016.12.
Caspase 7 (CASP7) expression has important function during cell cycle progression and cell growth in certain cancer cells and is also involved in the development and differentiation of dental tissues. However, the function of CASP7 in breast cancer cells is unclear. The aim of this study was to analyze the expression of CASP7 in breast carcinoma patients and determine the role of CASP7 in regulating tumorigenicity in breast cancer cells. In this study, we show that the CASP7 expression is high in breast carcinoma tissues compared with normal counterpart. The ectopic expression of CASP7 is significantly associated with ERα expression status and persistently elevated in different stages of the breast tumor grades. High level of CASP7 expression showed better prognosis in breast cancer patients with systemic endocrine therapy as observed from Kaplan-Meier analysis. S3 and S4, estrogen responsive element (ERE) in the CASP7 promoter, is important for estrogen-ERα-mediated CASP7 overexpression. Increased recruitment of p300, acetylated H3 and pol II in the ERE region of CASP7 promoter is observed after hormone stimulation. Ectopic expression of CASP7 in breast cancer cells results in cell growth and proliferation inhibition via p21(Cip) reduction, whereas small interfering RNA (siRNA) mediated reduction of CASP7 rescued p21(Cip) levels. We also show that pro- and active forms of CASP7 is located in the nucleus apart from cytoplasmic region of breast cancer cells. The proliferation and growth of breast cancer cells is significantly reduced by broad-spectrum peptide inhibitors and siRNA of CASP7. Taken together, our findings show that CASP7 is aberrantly expressed in breast cancer and contributes to cell growth and proliferation by downregulating p21(Cip) protein, suggesting that targeting CASP7-positive breast cancer could be one of the potential therapeutic strategies.
半胱天冬酶7（CASP7）的表达在某些癌细胞的细胞周期进程和细胞生长过程中具有重要作用，并且还参与牙组织的发育和分化。然而，CASP7在乳腺癌细胞中的功能尚不清楚。本研究的目的是分析CASP7在乳腺癌患者中的表达，并确定CASP7在调节乳腺癌细胞致瘤性中的作用。在本研究中，我们发现与正常组织相比，CASP7在乳腺癌组织中高表达。CASP7的异位表达与雌激素受体α（ERα）的表达状态显著相关，并且在不同分级的乳腺肿瘤阶段持续升高。从Kaplan-Meier分析可以观察到，高水平的CASP7表达在接受全身内分泌治疗的乳腺癌患者中显示出更好的预后。CASP7启动子中的雌激素反应元件（ERE）S3和S4对于雌激素-ERα介导的CASP7过表达很重要。激素刺激后，观察到CASP7启动子ERE区域中p300、乙酰化H3和RNA聚合酶II的募集增加。在乳腺癌细胞中异位表达CASP7会通过降低p21（Cip）导致细胞生长和增殖受到抑制，而小干扰RNA（siRNA）介导的CASP7降低则使p21（Cip）水平恢复。我们还表明，CASP7的前体形式和活性形式除了位于乳腺癌细胞的细胞质区域外，还位于细胞核中。CASP7的广谱肽抑制剂和siRNA可显著降低乳腺癌细胞的增殖和生长。综上所述，我们的研究结果表明，CASP7在乳腺癌中异常表达，并通过下调p21（Cip）蛋白促进细胞生长和增殖，这表明靶向CASP7阳性乳腺癌可能是一种潜在的治疗策略。
