Key Lab of the Ministry of Education for Coastal and Wetland Ecosystems, School of Life Sciences, Xiamen University, Xiangan South Road, Xiamen, 361102, Fujian, China.
Department of Gastroenterology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, Fujian, China.
Dig Dis Sci. 2018 Dec;63(12):3348-3358. doi: 10.1007/s10620-018-5254-6. Epub 2018 Aug 28.
Aberrant expression of retinoic acid receptor α (RARα) was correlated with diverse carcinomas such as acute promyelocytic leukemia and colorectal carcinoma. Nevertheless, the function and mechanism of RARα in esophageal carcinoma (EC) remain unclear.
To investigate the expression of RARα in EC and its effect in the tumorigenesis of EC.
In immunohistochemistry study, RARα was overexpressed in human EC tissues, and its overexpression was closely related to the pathological differentiation, lymph node metastasis, and clinical stages in EC patients. Functionally, RARα knockdown suppressed the proliferation and metastasis of EC cells through downregulating the expression of PCNA, Ki67, MMP7, and MMP9, as well as enhanced drug susceptibility of EC cells to 5-fluorouracil and cisplatin. Mechanistically, RARα knockdown inhibited the activity of Wnt/β-catenin pathway through reducing the phosphorylation level of GSK3β at Ser-9 and inducing phosphorylation level at Tyr-216, which resulted in downregulation of its downstream targets such as MMP7, MMP9, and P-gP.
Our results demonstrated that RARα knockdown suppressed the tumorigenicity of EC via Wnt/β-catenin pathway. RARα might be a potential molecular target for EC clinical therapy.
维甲酸受体 α（RARα）的异常表达与多种癌症相关，如急性早幼粒细胞白血病和结直肠癌。然而，RARα在食管癌（EC）中的功能和机制仍不清楚。
研究 RARα在 EC 中的表达及其在 EC 发生中的作用。
在免疫组织化学研究中，RARα在人 EC 组织中过度表达，其过度表达与 EC 患者的病理分化、淋巴结转移和临床分期密切相关。功能上，RARα 敲低通过下调 PCNA、Ki67、MMP7 和 MMP9 的表达，以及增强 EC 细胞对 5-氟尿嘧啶和顺铂的敏感性，抑制 EC 细胞的增殖和转移。在机制上，RARα 敲低通过降低 GSK3β 在 Ser-9 处的磷酸化水平和诱导 Tyr-216 处的磷酸化水平，抑制 Wnt/β-catenin 通路的活性，导致其下游靶标 MMP7、MMP9 和 P-gP 的下调。
我们的结果表明，RARα 敲低通过 Wnt/β-catenin 通路抑制 EC 的致瘤性。RARα 可能是 EC 临床治疗的潜在分子靶点。
