Abstract
Although the upregulated expression of Anxa2 has been implicated in carcinogenesis, cancer progression, and poor prognosis of cancer patients, the detailed molecular mechanisms involved in these processes remain unclear. In this study, we investigated the effect of Anxa2 downregulation with small interference RNA on breast cancer proliferation. To explore molecular mechanisms underlying Anxa2-mediated cancer cell proliferation. We analyzed cell cycle distribution and signaling pathways using semi-quantitative real-time PCR and Western blotting. Anxa2 depletion in breast cancer cells significantly inhibited cell proliferation by decelerating cell cycle progression. The retarded G1-to-S phase transition in Anxa2-silenced cells was attributed to the decreased levels of cyclin D1, which is a crucial promoting factor for cell proliferation because it regulates G1-to-S phase transition during cell cycle progression. We provided evidence that Anxa2 regulates epidermal growth factor-induced phosphorylation of STAT3. The reduced expression of phosphorylated STAT3 is the main factor responsible for decreased cyclin D1 levels in Anxa2-silenced breast cancer cells. Our results revealed the direct relationship between Anxa2 and activation of STAT3, a key transcription factor that plays a pivotal role in regulating breast cancer proliferation and survival. This study provides novel insights into the functions of Anxa2 as a critical molecule in cellular signal transduction and significantly improves our understanding of the mechanism through which Anxa2 regulates cell cycle and cancer cell proliferation.
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Acknowledgments
This research was supported by grants from the National Natural Science Foundation of China (Nos. 81372844, and 81472474), Tianjin Municipal Science and Technology Commission (Nos. 12JCZDJC24500 and 12JCQNJC07000), Changjiang Scholars and Innovative Research Team (IRT1076), 863 Project (2012AA020206-5), Specialized Research Fund for the Doctoral Program of Higher Education (20131202110002).
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Fei Zhang and Zhiyong Wang have contributed equally to this work.
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Zhang, F., Wang, Z., Yuan, J. et al. RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway. Breast Cancer Res Treat 153, 263–275 (2015). https://doi.org/10.1007/s10549-015-3529-6
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DOI: https://doi.org/10.1007/s10549-015-3529-6