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

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.

A Methylation-based nomogram for predicting survival in patients with lung adenocarcinoma

“…As shown in Fig. 2B, KEGG pathway enrichment analysis found twelve signi cantly enriched pathways related to cancer progression, such as PI3K-Akt signaling pathway [23,24], ECM-receptor interaction [25,26] and p53 signaling pathway [27,28]. The results indicated that these DEGs played key roles in multiple cancer-related pathways, and further indicated that the DMSs might be involved in LUAD progression by regulating the corresponding gene expression.…”

Downregulation of CENPK suppresses lung adenocarcinoma by regulating EMT

“…Western blotting was performed according to a previous description [30]. Briefly, whole cell lysates were normalized by OD600.…”

Connexins in Lung Cancer and Brain Metastasis

“…However, there are very limited published studies concerning the regulatory mechanism of Cx43 during lung cancer development. Hypoxia activates the P53/MDM2 axis and induces Cx43 internalization ( 31 ). Cx43 is moved from the membrane to cytoplasm, where it is degraded ( 31 ), and the lower Cx43 levels promote EMT, inducing proliferation and tumorigenicity in human NSCLC tissue and cells ( 31 ).…”

“…Hypoxia activates the P53/MDM2 axis and induces Cx43 internalization ( 31 ). Cx43 is moved from the membrane to cytoplasm, where it is degraded ( 31 ), and the lower Cx43 levels promote EMT, inducing proliferation and tumorigenicity in human NSCLC tissue and cells ( 31 ). In contrast, p38 MAPK activation and JNK inhibition increases Cx43-mediated cell-cell communication via in human lung neoplastic cells and this activation is induced by 4-phenyl-3-butenoic acid ( 32 ).…”

“…In addition to Cx43, other Cx subtypes are also involved in lung cancer cell proliferation, EMT, tumorgenicity, and metastasis. In hypoxia induced human pulmonary epithelial cells, low levels of Cx26 promoted EMT, inducing proliferation and tumorigenicity of cancer cells ( 31 ). In the A549 NSCLC-ad cell line expressing Cx26, the PI3K/AKT signaling pathway is involved in EMT ( 18 ).…”