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Bicarbonate transporter SLC4A7 promotes EMT and metastasis of HNSCC by activating the PI3K/AKT/mTOR signaling pathway |
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| Authors: | Junli Hu Guo Li Zhifeng Liu Huiling Ma Wenhui Yuan Zhaoyi Lu Diekuo Zhang Hang Ling Fengyu Zhang Yong Liu Chao Liu Yuanzheng Qiu |
| Affiliation: | 1. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, China Department of Otolaryngology Head and Neck Surgery, Yantian District People's Hospital, Shenzhen, Guangdong, China;2. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, China National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China;3. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, China;4. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China |
| Abstract: | Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Currently, therapeutic modalities such as surgery, chemotherapy, radiotherapy, and immunotherapy are being used to treat HNSCC. However, the treatment outcomes of most patients are dismal because they are already in middle or advanced stage by the time of diagnosis and poorly responsive to treatments. It is therefore of great interest to clarify mechanisms that contribute to the metastasis of cells to identify possible targets for therapy. In this study, we identified the Na+-coupled bicarbonate transporter, SLC4A7, play essential roles in the metastasis of HNSCC. Our results showed that the relative expression of SLC4A7 messenger RNA was highly expressed in HNSCCs samples from TCGA, and compared with precancerous cells of human oral mucosa (DOK), SLC4A7 was highly expressed in HNSCC cell lines. In vitro and in vivo experiments showed that dysregulation of SLC4A7 had minor influence on the proliferation of HNSCC but impacted HNSCC's migration and invasion. Meanwhile, SLC4A7 could promote epithelial-mesenchymal transition (EMT) in HNSCC. RNA-seq, KEGG pathway enrichment analysis and Western blot further revealed that downregulation of SLC4A7 in HNSCC cells inhibited the PI3K/AKT pathway. These findings were further validated via rescue experiments using a small molecule inhibitor of PI3K/mTOR (GDC-0980). Our findings suggest that SLC4A7 promotes EMT and metastasis of HNSCC through the PI3K/AKT/mTOR signaling pathway, which may be a valuable predictive biomarker and potential therapeutic target in HNSCC. |
| Keywords: | epithelial-mesenchymal transition head and neck squamous cell carcinoma metastasis PI3K/AKT/mTOR signaling pathway SLC4A7 |