Abdul Rahman Mariati, Tan May Leng, Johnson Steven P, Hollows Robert J, Chai Wen Lin, Mansell Jason P, Yap Lee Fah, Paterson Ian C
Department of Oral and Craniofacial Sciences, University of Malaya, Kuala Lumpur, Malaysia.
Department of Craniofacial Diagnostics and Biosciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
PeerJ. 2020 Nov 11;8:e10328. doi: 10.7717/peerj.10328. eCollection 2020.
Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide and accounts for 300,000 new cases yearly. The five-year survival rate is approximately 50% and the major challenges to improving patient prognosis include late presentation, treatment resistance, second primary tumours and the lack of targeted therapies. Therefore, there is a compelling need to develop novel therapeutic strategies. In this study, we have examined the effect of lysophosphatidic acid (LPA) on OSCC cell migration, invasion and response to radiation, and investigated the contribution of cyclooxygenase-2 (COX-2) in mediating the tumour promoting effects of LPA. Using the TCGA data set, we show that the expression of the lipid phosphate phosphatases (LPP), LPP1 and LPP3, was significantly down-regulated in OSCC tissues. There was no significant difference in the expression of the ENPP2 gene, which encodes for the enzyme autotaxin (ATX) that produces LPA, between OSCCs and control tissues but ENPP2 levels were elevated in a subgroup of OSCCs. To explore the phenotypic effects of LPA, we treated OSCC cell lines with LPA and showed that the lipid enhanced migration and invasion as well as suppressed the response of the cells to irradiation. We also show that LPA increased COX-2 mRNA and protein levels in OSCC cell lines and inhibition of COX-2 activity with the COX-2 inhibitor, NS398, attenuated LPA-induced OSCC cell migration. Collectively, our data show for the first time that COX-2 mediates some of the pro-tumorigenic effects of LPA in OSCC and identifies the ATX-LPP-LPA-COX-2 pathway as a potential therapeutic target for this disease.
口腔鳞状细胞癌（OSCC）是全球第六大常见癌症，每年新增病例达30万例。其五年生存率约为50%，改善患者预后的主要挑战包括就诊延迟、治疗抵抗、第二原发性肿瘤以及缺乏靶向治疗。因此，迫切需要开发新的治疗策略。在本研究中，我们检测了溶血磷脂酸（LPA）对OSCC细胞迁移、侵袭及辐射反应的影响，并研究了环氧合酶-2（COX-2）在介导LPA的促肿瘤作用中的作用。利用TCGA数据集，我们发现脂质磷酸磷酸酶（LPP）中的LPP1和LPP3在OSCC组织中的表达显著下调。编码产生LPA的自分泌运动因子（ATX）的ENPP2基因在OSCC组织与对照组织中的表达无显著差异，但在一部分OSCC中ENPP2水平升高。为了探究LPA的表型效应，我们用LPA处理OSCC细胞系，结果显示该脂质增强了细胞的迁移和侵袭能力，并抑制了细胞对辐射的反应。我们还发现LPA可提高OSCC细胞系中COX-2的mRNA和蛋白水平，用COX-2抑制剂NS398抑制COX-2活性可减弱LPA诱导的OSCC细胞迁移。总的来说，我们的数据首次表明COX-2介导了LPA在OSCC中的一些促肿瘤作用，并确定了ATX-LPP-LPA-COX-2途径是该疾病的一个潜在治疗靶点。
