State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Biochem Biophys Res Commun. 2023 Nov 12;681:80-89. doi: 10.1016/j.bbrc.2023.09.041. Epub 2023 Sep 20.
Studies suggest that the expression of glutamate decarboxylase 1 (GAD1), γ-aminobutyric acid (GABA), and GABA receptors are involved in tumor progression. However, the underlying mechanisms of high expression and potential functions of GAD1 and GABA in oral squamous cell carcinoma (OSCC) are not known. In this study, we found that the expressions of GAD1 and GABA were considerably increased in OSCC samples, which were closely associated with clinical stage and lymph node metastasis. The knockdown of GAD1 expression significantly inhibited the proliferation, migration and invasion abilities of OSCC cells by reducing the expression of GABA-mediated GABA receptors, which could be reversed by exogenous GABA, but did not cause excessive OSCC cell proliferation. And GABA secreted by OSCC cells promoted M2 macrophage polarization for inhibiting anti-tumor immunity by activating GABBR1/ERK/Ca. In addition, GABA/GABAR promoted the proliferation and progression of OSCC xenograft tumor. Altogether, our results showed that GAD1 synthetized GABA to promote the malignant progression of OSCC and limits the anti-tumor immunity of macrophages, thereby targeting GABA can be a novel strategy for treating OSCC.
研究表明，谷氨酸脱羧酶 1（GAD1）、γ-氨基丁酸（GABA）和 GABA 受体的表达与肿瘤进展有关。然而，GAD1 和 GABA 在口腔鳞状细胞癌（OSCC）中高表达的潜在机制及其功能尚不清楚。在本研究中，我们发现 GAD1 和 GABA 的表达在 OSCC 样本中显著增加，与临床分期和淋巴结转移密切相关。GAD1 表达的下调通过降低 GABA 介导的 GABA 受体的表达显著抑制了 OSCC 细胞的增殖、迁移和侵袭能力，外源性 GABA 可逆转这一作用，但不会引起 OSCC 细胞过度增殖。并且 OSCC 细胞分泌的 GABA 通过激活 GABBR1/ERK/Ca 促进 M2 巨噬细胞极化，从而抑制抗肿瘤免疫。此外，GABA/GABAR 促进了 OSCC 异种移植肿瘤的增殖和进展。总的来说，我们的研究结果表明，GAD1 合成 GABA 促进了 OSCC 的恶性进展，并限制了巨噬细胞的抗肿瘤免疫，因此靶向 GABA 可能是治疗 OSCC 的一种新策略。
