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K-Ras promotes the non-small lung cancer cells survival by cooperating with sirtuin 1 and p27 under ROS stimulation

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Tumor Biology

Abstract

Cigarette smoking might lead to lung cancer. However, the related signaling pathways at molecular level remained unknown until now. In this study, we studied the signaling processes associated between tobacco exposure and lung cancer. First, we detected and validated pathway-specific gene expression at bronchial epithelium. These proteins reflected the activation of signaling pathways relevant to tobacco exposure, including ATM, BCL2, GPX1, K-Ras, IKBKB, and SIRT1. Tobacco smoking was simulated via reactive oxygen species (ROS) pathway. ROS not only arrested cell cycle at G1/S stage but also increased expressions of Sirt1 and p27. Further studies showed that the expression of p27 was dependent on ERK1/2 activation, and p27 itself could halt cell cycle by inhibiting the activation of CDKs. Moreover, activation of K-Ras, the key regulator of Ras/ERK pathway, was tightly regulated by enzyme activity of Sirt1. Deacetylation of K-Ras by Sirt1 increased the transformation of Ras-GTP to Ras-GDP, promoting the activation of downstream of ERK1/2. In reverse, Ras/ERK pathway could also regulate Sirt1 transcription. In conclusion, inhibition of Sirt1 may be an effective strategy for the prevention of tumor progression in high-risk patients or as a therapeutic strategy in established tumors.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (NO. 81373075, 81371748). This work was supported by grants from the Natural Science Foundation of Zhejiang Province (NO. LY14H16042, Y12H310019).

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Authors and Affiliations

  1. Laboratory for Interdisciplinary Research, Institution for Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, No. 2 of Fuxue Lane, Wenzhou City, Zhejiang Province, 325000, China

    Dezhi Cheng, Liang Zhao, Yunsheng Xu, Rongying Ou & Wenfeng Li

  2. Department of Thoracic Cardiovascular, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Dezhi Cheng

  3. PET/CT Division of Imaging Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Liang Zhao

  4. Institution for Digital and Molecular Imaging, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Liang Zhao

  5. Department of Dermatovenerology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Yunsheng Xu

  6. Gynaecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Rongying Ou

  7. Department of Chemoradiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Gang Li, Han Yang & Wenfeng Li

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  1. Dezhi Cheng
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  2. Liang Zhao
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  5. Gang Li
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  7. Wenfeng Li
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Correspondence to Wenfeng Li.

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Cheng, D., Zhao, L., Xu, Y. et al. K-Ras promotes the non-small lung cancer cells survival by cooperating with sirtuin 1 and p27 under ROS stimulation. Tumor Biol. 36, 7221–7232 (2015). https://doi.org/10.1007/s13277-015-3429-8

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  • DOI: https://doi.org/10.1007/s13277-015-3429-8

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