Abstract
The poor prognosis of head and neck squamous cell carcinoma (HNSCC) is partly due to the lack of reliable predictive markers. Connexin 43 (Cx43) protein and its cell-communication channels have been assigned tumor suppressor functions while the anti-apoptotic Bcl-2 (B-cell lymphoma-2) protein has been associated with negative prognostic significance in cancer. This study aimed to test the role of Cx43 protein on Bcl-2 expression, tumor progression and response to taxane-based treatment in HNSCC. Human papillomavirus (HPV) negative HNSCC cell lines were tested for paclitaxel sensitivity through measuring apoptosis induction, cell viability and changes in Cx43 and Bcl-2 levels using flow cytometry, cell viability assay, immunocytochemistry and western blot. Inhibition of Cx43 expression using siRNA increased Bcl-2 protein levels in SCC25 (tongue squamous cell carcinoma) cells, while forced Cx43 expression reduced Bcl-2 levels and supported paclitaxel cytotoxicity in FaDu (hypopharynx squamous cell carcinoma) cells. In vitro results were in line with protein expression and clinicopathological features tested in tissue microarray samples of HNSCC patients. Our data demonstrate that elevated Cx43 and reduced Bcl-2 levels may indicate HNSCC sensitivity to taxane-based treatments. On the contrary, silencing of the Cx43 gene GJA1 (gap junction protein alpha-1) can result in increased Bcl-2 expression and reduced paclitaxel efficiency. Clinical tumor-based analysis also confirmed the inverse correlation between Cx43 and Bcl-2 expression.
Highlights
An estimated 600,000 new head and neck cancers are diagnosed annually worldwide [1]
Expression of Connexin 43 (Cx43) is low in Detroit 562 and FaDu, as opposed to SCC25 with high protein expression
[23]. could be regarded as a prognostic factor in head and In neck and the reduction of itsCx43 expression level is associated with a significantly poorer ourcancers, previous study, we found that could be regarded as a prognostic factor in head and prognosis
Summary
An estimated 600,000 new head and neck cancers (tumors of the lip, oral cavity, larynx, nasopharynx, oropharynx and hypopharynx) are diagnosed annually worldwide [1]. Modern, targeted therapy drugs—such as the Food and Drug Administration (FDA) approved cetuximab—shows clear benefit only for the treatment of recurrent or metastatic head and neck cancers as first line therapy compared to chemotherapy [3]. (cytotoxic T-lymphocyte-associated antigen 4) antibodies) demonstrated clinical benefit and were approved by FDA for patients with HNSCCs (head and neck squamous cell carcinoma) which showed progression after treatment with platinum-based chemotherapy. Chemoradiotherapy (CRT) is still the most often used non-surgical therapeutic choice in locoregionally advanced HNSCC. No biomarker is available to predict the therapeutic response, resulting in a substantial number of patients who suffer the side effects of such a toxic treatment without clinical benefit.
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