Intrinsic Oncogenic Function of Intracellular Connexin26 Protein in Head and Neck Squamous Cell Carcinoma Cells

• Published in: International journal of molecular sciences 2018-07, Vol.19 (7), p.2134
• Main Authors: Iikawa, Nobuko, Yamamoto, Yohei, Kawasaki, Yohei, Nishijima-Matsunobu, Aki, Suzuki, Maya, Yamada, Takechiyo, Omori, Yasufumi
• Format: Article
• Language: English
• Subjects: Amino acid sequence; Amino acids; Breast cancer; C-Terminus; cancer progression; Carcinogenesis; Carcinogens; Cell growth; Cell membranes; Cell proliferation; Cell signaling; cell-cell communication; Cloning; Communication; connexin26; Connexins; Cytoplasm; Endoplasmic reticulum; ER-Golgi retention signal; Esophagus; gap junction; Gap junctions; Genotype & phenotype; Golgi apparatus; Head & neck cancer; head and neck squamous cell carcinoma; Immunofluorescence; Intracellular; Kinases; Liver cancer; Membrane proteins; Metastasis; Mutation; Nuclei (cytology); Otolaryngology; Phenotypes; Proteins; Retention; Squamous cell carcinoma; Stem cells; Tumorigenicity; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19072134

It has long been known that the gap junction is down-regulated in many tumours. One of the downregulation mechanisms is the translocation of connexin, a gap junction protein, from cell membrane into cytoplasm, nucleus, or Golgi apparatus. Interestingly, as tumours progress and reinforce their malignant phenotype, the amount of aberrantly-localised connexin increases in different malignant tumours including oesophageal squamous cell carcinoma, thus suggesting that such an aberrantly-localised connexin should be oncogenic, although gap junctional connexins are often tumour-suppressive. To define the dual roles of connexin in head and neck squamous cell carcinoma (HNSCC), we introduced the wild-type connexin26 (wtCx26) or the mutant Cx26 (icCx26) gene, the product of which carries the amino acid sequence AKKFF, an endoplasmic reticulum-Golgi retention signal, at the C-terminus and is not sorted to cell membrane, into the human FaDu hypopharyngeal cancer cell line that had severely impaired the expression of connexin during carcinogenesis. wtCx26 protein was trafficked to the cell membrane and formed gap junction, which successfully exerted cell-cell communication. On the other hand, the icCx26 protein was co-localised with a Golgi marker, as revealed by immunofluorescence, and thus was retained on the way to the cell membrane. While the forced expression of wtCx26 suppressed both cell proliferation in vitro and tumorigenicity in mice in vivo, icCx26 significantly enhanced both cell proliferation and tumorigenicity compared with the mock control clones, indicating that an excessive accumulation of connexin protein in intracellular domains should be involved in cancer progression and that restoration of proper subcellular sorting of connexin might be a therapeutic strategy to control HNSCC.