Open Access

Hypoxia‑induced internalization of connexin 26 and connexin 43 in pulmonary epithelial cells is involved in the occurrence of non‑small cell lung cancer via the P53/MDM2 signaling pathway

  • Authors:
    • Shang‑Gan Zeng
    • Xiang Lin
    • Ji‑Chun Liu
    • Jin Zhou
  • View Affiliations

  • Published online on: September 3, 2019     https://doi.org/10.3892/ijo.2019.4867
  • Pages: 845-859
  • Copyright: © Zeng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Reports have highlighted an association between connexins (CXs) or gap junction proteins and non‑small cell lung cancer (NSCLC). In the present study, it was aimed to elucidate the regulatory mechanism of CX26 and CX43 under hypoxic conditions in NSCLC. Clinical samples were collected for analysis of CX26 and CX43 expression and clinical cancerization followed by quantification of CX26 and CX43 expression. Following the establishment of an in vitro hypoxia model, P53/murine double minute‑2 (MDM2) signaling pathway‑, proliferation‑ and epithelial‑mesenchymal transition (EMT)‑related genes were quantified to evaluate the influence of CX26 and CX43 on the biological functions of pulmonary epithelial cells in NSCLC. In addition, the proliferation and tumorigenicity of cancer cells were assessed by EdU staining and xenograft tumors, respectively. Decreased expression of CX26 and CX43 was found in cancer tissues compared with surrounding normal tissue. Hypoxia was shown to activate the P53/MDM2 axis and stimulate the downregulation, ubiquitination and degradation of CX26 and CX43, which were translocated from the membrane to the cytoplasm. Low levels of CX26 and CX43 were demonstrated to further promote EMT and the induction of the proliferation and tumorigenicity of cancer cells. These results were reflected by decreased E‑cadherin expression and increased N‑cadherin expression, along with increased cell migration, promoted cell proliferation ability and elevated relative protein expression of Oct4 and Nanog, and accelerated tumor growth, accompanied by a higher number of metastatic nodes. Taken together, the key observations of the present study demonstrate that the internalization of CX26 and CX43 promoted proliferation, EMT and migration and thus induced NSCLC via aberrant activation of the P53/MDM2 signaling pathway under hypoxic conditions.

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October 2019
Volume 55 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Zeng, S., Lin, X., Liu, J., & Zhou, J. (2019). Hypoxia‑induced internalization of connexin 26 and connexin 43 in pulmonary epithelial cells is involved in the occurrence of non‑small cell lung cancer via the P53/MDM2 signaling pathway. International Journal of Oncology, 55, 845-859. https://doi.org/10.3892/ijo.2019.4867
MLA
Zeng, S., Lin, X., Liu, J., Zhou, J."Hypoxia‑induced internalization of connexin 26 and connexin 43 in pulmonary epithelial cells is involved in the occurrence of non‑small cell lung cancer via the P53/MDM2 signaling pathway". International Journal of Oncology 55.4 (2019): 845-859.
Chicago
Zeng, S., Lin, X., Liu, J., Zhou, J."Hypoxia‑induced internalization of connexin 26 and connexin 43 in pulmonary epithelial cells is involved in the occurrence of non‑small cell lung cancer via the P53/MDM2 signaling pathway". International Journal of Oncology 55, no. 4 (2019): 845-859. https://doi.org/10.3892/ijo.2019.4867