Association of STAT3 with Cx26 and Cx43 in human uterine endometrioid adenocarcinoma

Sulkowska, Urszula; Febp, Andrzej Wincewicz; Sulkowski, Stanisław

doi:10.3892/ol.2016.4550

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…The CX-CX interaction mechanism has been revealed to be important in intercellular communication regulation; for instance, CX26 can be co-expressed with CX43 in human skin (9). Researchers have highlighted the role of CX26 and CX43 signaling in the suppression of tumor progression (10). In recent years, the interaction between the tumor suppressor gene P53 and its negative regulator, murine double minute-2 (MDM2), has been reported as a potential therapeutic target for patients with cancer (11).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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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Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Tissue sections were immunostained with anti-alpha smooth muscle actin (α-SMA), anti-LDH-B, and anti-Cx43 antibodies. A scoring system was used to describe both the staining intensity (negative, weak, moderate, or strong) and the proportion of tumor cells (Cx43: 0%, <10%, 10-50%, or >50%; α-SMA: <5%, 5-25%, 26-50%, or >50%; LDH-B: 0%, <10%, 10-50%, or >50%) stained in each case as described previously [36,37,38]. An Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry immunohistochemistry score was then assigned to each sample by multiplying the proportion score and intensity score.…”

Section: Activity Assaysmentioning

confidence: 99%

Cancer-Associated Fibroblasts Accelerate Malignant Progression of Non-Small Cell Lung Cancer via Connexin 43-Formed Unidirectional Gap Junctional Intercellular Communication

Luo

Mao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Gap junctions, which are assembled by connexins, can directly connect the cytoplasm of adjacent cells and enable gap junctional intercellular communication (GJIC) as well as metabolic coupling between neighboring cells. Here, we investigated the role of connexin 43 (Cx43) and its derived GJIC in the interplay between non-small cell lung cancer (NSCLC) cells and cancer-associated fibroblasts (CAFs). Methods: CAFs and NSCLC cells were co-cultured with direct contact and separated using flow cytometry. Glucose uptake, lactate production, and the expression and activity of PKM-2 and LDH-A in sorted CAFs were measured by a colorimetric assay, western blotting, and enzyme-linked immunosorbent assay (ELISA). Meanwhile, E-cadherin and N-cadherin expression and the migration and invasion of sorted NSCLC cells were detected by western blotting, wound width, and Transwell assays. Pyruvate, acetyl-CoA, and citric acid levels, ATP levels, and LDH-B and α-KG activity in sorted NSCLC cells were determined by a colorimetric or fluorometric assay and ELISA, respectively. Functional GJIC between cells and the subcellular location of connexins were detected by a “Parachute” assay and immunofluorescence. Levels of α-SMA, Cx43, and LDH-B in tissue from patients with NSCLC were determined by immunohistochemistry. Results: Cx43 accumulated in the plasma membrane, which favored the assembly of asymmetric unidirectional GJIC from CAFs to NSCLC cells. CAFs underwent increased aerobic glycolysis and promoted the epithelial-mesenchymal transition, migration, and invasion of NSCLC cells. In contrast, NSCLC cells experienced enhanced oxidative phosphorylation upon CAF stimulation, with an increase in ATP generation and thereby activation of the PI3K/Akt and MAPK/ERK pathways. Metabolic coupling between CAFs and NSCLC cells was under the strict control of Cx43-formed unidirectional GJIC. Patients with high tri-expression of α-SMA, Cx43, and LDH-B had the shortest overall survival and relapse-free survival compared with those with individual overexpression or high bi-expression. Conclusion: Cx43-formed unidirectional GJIC plays a critical role in mediating close metabolic cooperation between CAFs and NSCLC cells to support the malignant progression of NSCLC.

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“…This novel role of PI3k and Stat3 may be an important regulatory step in the progression of tumours that exploit such a pathway. In fact, a correlation was noted between nuclear Stat3 levels and Cx43 and Cx26 in grade 1 and 2 uterine endometrioid adenocarcinomas, while this association was progressively weaker as the tumors dedifferentiated to G3, presumably due to the activation of additional oncogenes [109].…”

Section: Discussionmentioning

confidence: 99%

PI3k and Stat3: Oncogenes that are Required for Gap Junctional, Intercellular Communication

Geletu

Taha

Gunning

et al. 2019

Cancers

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Gap junctional, intercellular communication (GJIC) is interrupted in cells transformed by oncogenes such as activated Src. The Src effector, Ras, is required for this effect, so that Ras inhibition restores GJIC in Src-transformed cells. Interestingly, the inhibition of the Src effector phosphatidyl-inositol-3 kinase (PI3k) or Signal Transducer and Activator of Transcription-3 (Stat3) pathways does not restore GJIC. In the contrary, inhibition of PI3k or Stat3 in non-transformed rodent fibroblasts or epithelial cells or certain human lung carcinoma lines with extensive GJIC inhibits communication, while mutational activation of PI3k or Stat3 increases GJIC. Therefore, it appears that oncogenes such as activated Src have a dual role upon GJIC; acting as inhibitors of communication through the Ras pathway, and as activators through activation of PI3k or Stat3. In the presence of high Src activity the inhibitory functions prevail so that the net effect is gap junction closure. PI3k and Stat3 constitute potent survival signals, so that their inhibition in non-transformed cells triggers apoptosis which, in turn, has been independently demonstrated to suppress GJIC. The interruption of gap junctional communication would confine the apoptotic event to single cells and this might be essential for the maintenance of tissue integrity. We hypothesize that the GJIC activation by PI3k or Stat3 may be linked to their survival function.

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Association of STAT3 with Cx26 and Cx43 in human uterine endometrioid adenocarcinoma

Cited by 5 publications

References 25 publications

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

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

Cancer-Associated Fibroblasts Accelerate Malignant Progression of Non-Small Cell Lung Cancer via Connexin 43-Formed Unidirectional Gap Junctional Intercellular Communication

PI3k and Stat3: Oncogenes that are Required for Gap Junctional, Intercellular Communication

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