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Bicarbonate transporter SLC4A7 promotes EMT and metastasis of HNSCC by activating the PI3K/AKT/mTOR signaling pathway

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.

 

Comments：

This study identifies the Na+-coupled bicarbonate transporter, SLC4A7, as playing essential roles in the metastasis of head and neck squamous cell carcinoma (HNSCC). The study shows that SLC4A7 is highly expressed in HNSCC cells and promotes their migration and invasion, as well as epithelial-mesenchymal transition (EMT) in vitro and in vivo. The study also reveals that downregulation of SLC4A7 in HNSCC cells inhibits the PI3K/AKT pathway, and that this pathway can be targeted using a small molecule inhibitor of PI3K/mTOR (GDC-0980).

These findings suggest that SLC4A7 may be a valuable predictive biomarker and potential therapeutic target in HNSCC. This is important because the treatment outcomes of most patients with HNSCC are currently poor, and identifying new therapeutic targets is essential to improve patient outcomes.

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S2696 Apitolisib (GDC-0980) Apitolisib (GDC-0980, RG7422, GNE 390) is a potent, class I PI3K inhibitor for PI3Kα/β/δ/γ with IC50 of 5 nM/27 nM/7 nM/14 nM in cell-free assays, respectively. Also a mTOR inhibitor with Ki of 17 nM in a cell-free assay, and highly selective versus other PIKK family kinases. Apitolisib activates autophagy and apoptosis simultaneously in pancreatic cancer cells. Phase 2.

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