Vishwakarma Supriya, Joshi Deepti, Pandey Ritu, Das Saikat, Mukhopadhyay Sramana, Rai Renu, Singhal Ritu, Kapoor Neelkamal, Kumar Ashok
Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, IND.
Department of Pathology and Laboratory Medicine, All India Institute of Medical Sciences, Bhopal, IND.
Cureus. 2022 Mar 27;14(3):e23553. doi: 10.7759/cureus.23553. eCollection 2022 Mar.
Background Sphingosine-1-phosphate (S1P) is a potent oncogenic lipid. Intracellular levels of S1P are tightly regulated by eight S1P-metabolizing enzymes. S1P synthesis is catalyzed by two sphingosine kinases, i.e., sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2). Five lipid phosphatases (two S1P phosphatases and lipid phosphate phosphatases (LPPs) 1, 2, and 3) reversibly convert S1P back to sphingosine. Previously, we have determined the mRNA expression profile of eight S1P-metabolizing enzymes in tumor tissues and adjacent normal tissues from oral squamous cell carcinoma (OSCC) patients. Except for SphK1, the role of S1P-metabolizing enzymes in OSCC has been poorly studied. Methods We have determined the protein expression of four S1P-metabolizing enzymes (SphK1, SphK2, sphingosine-1-phosphate phosphatase 1 (SGPP1), and lipid phosphate phosphatase 3 (LPP3)) by immunohistochemistry (IHC) in tumor tissues of 46 OSCC patients. Six subjects with non-dysplastic oral mucosa were also included in the study. The immunoreactivity score (IRS) was calculated for each protein in every subject. Further, we determined the associations of expression of S1P-metabolizing enzymes with clinicopathological features of OSCC patients. Results We demonstrate the low IRS for SphK2 and LPP3 in OSCC tumors. Importantly, expression of SphK2 and LPP3 was downregulated in malignant epithelial cells compared to non-malignant mucosa. Further, LPP3 expression negatively correlated with tumor‑node‑metastasis (TNM) staging of patients (r = -0.307, p = 0.043). Importantly, expression of LPP3 in tumors was found to be an independent predictor of perinodal extension (b = -0.440, p = 0.009), lymphovascular invasion (b = -0.614, p < 0.001), lymph node ratio (b = 0.336, p = 0.039), and TNM staging (b = -0.364, p = 0.030). Conclusion Taken together, our data show that expression of SphK2 and LPP3 is decreased compared to normal mucosa. Thus, the S1P signaling pathway could represent a potential therapeutic target.
鞘氨醇-1-磷酸（S1P）是一种强效的致癌脂质。细胞内S1P水平由八种S1P代谢酶严格调控。S1P的合成由两种鞘氨醇激酶催化，即鞘氨醇激酶1（SphK1）和鞘氨醇激酶2（SphK2）。五种脂质磷酸酶（两种S1P磷酸酶以及脂质磷酸磷酸酶（LPP）1、2和3）可将S1P可逆地转化回鞘氨醇。此前，我们已确定了口腔鳞状细胞癌（OSCC）患者肿瘤组织及癌旁正常组织中八种S1P代谢酶的mRNA表达谱。除SphK1外，S1P代谢酶在OSCC中的作用研究较少。
我们通过免疫组织化学（IHC）检测了46例OSCC患者肿瘤组织中四种S1P代谢酶（SphK1、SphK2、鞘氨醇-1-磷酸磷酸酶1（SGPP1）和脂质磷酸磷酸酶3（LPP3））的蛋白表达。该研究还纳入了6名口腔黏膜无异型增生的受试者。计算每个受试者每种蛋白的免疫反应评分（IRS）。此外，我们确定了S1P代谢酶表达与OSCC患者临床病理特征之间的关联。
我们发现OSCC肿瘤中SphK2和LPP3的IRS较低。重要的是，与非恶性黏膜相比，恶性上皮细胞中SphK2和LPP3的表达下调。此外，LPP3表达与患者的肿瘤-淋巴结-转移（TNM）分期呈负相关（r = -0.307，p = 0.043）。重要的是，肿瘤中LPP3的表达是结周扩展（b = -0.440，p = 0.009）、淋巴管浸润（b = -0.614，p < 0.001）、淋巴结比例（b = 0.336，p = 0.039）和TNM分期（b = -0.364，p = 0.030）的独立预测指标。
综上所述，我们的数据表明，与正常黏膜相比，SphK2和LPP3的表达降低。因此，S1P信号通路可能是一个潜在的治疗靶点。
