Zeng Yun-Zhu, Zhang Yong-Qu, Chen Jiong-Yu, Zhang Li-Ying, Gao Wen-Liang, Lin Xue-Qiong, Huang Shao-Min, Zhang Fan, Wei Xiao-Long
Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, China.
Department of Breast-Thyroid-Surgery and Cancer Research Center, Xiang'an Hospital of Xiamen University, Xiamen, China.
Front Oncol. 2021 Mar 29;11:627713. doi: 10.3389/fonc.2021.627713. eCollection 2021.
In China, over 90% of esophageal cancer (EC) cases are esophageal squamous cell carcinoma (ESCC). ESCC is a frequently malignant tumor with poor prognosis despite the development of comprehensive therapeutic strategies, for which there is still a lack of effective prognostic factors. Previous studies found that the abnormal expression of TRPC1 is closely related to the proliferation, invasion, metastasis, and differentiation of various tumors. However, the relationship between TRPC1 and ESCC is currently unclear. The present study aimed to clarify the clinical significance of TRPC1 and to preliminarily assess the molecular mechanism by which TRPC1 regulates cell proliferation, migration, and invasion in ESCC.
Immunohistochemistry (IHC) was used to determine the expression of TRPC1 and Ki-67 in 165 cases of ESCC. The correlations between TRPC1 expression and clinicopathological characteristics were determined, and both univariate and multivariate analyses were utilized to quantify the impact of TRPC1 expression on patient survival. Cell Counting Kit-8, scratch wound healing, and transwell assays were used to determine the effects of TRPC1 on proliferation, migration, and invasion in ESCC , respectively.
The positive expression rate of TRPC1 showed significantly decreased in ESCC (45.50%) compared with the levels in normal esophageal mucosa (NEM; 80.80%) and high-grade intraepithelial neoplasia (HGIEN; 63.20%) (<0.001). Higher expression rate of TRPC1 was associated with low lymph node metastasis (<0.001), high differentiation ( = 0.232, =0.003), and low Ki-67 ( = -0.492, <0.001). We further revealed that low expression of TRPC1 was associated with poor prognosis (Disease-free survival, DFS: 95% CI=0.545-0.845, =0.001; Overall survival, OS: 95% CI=0.553-0.891, =0.004). Furthermore, we showed that downregulation of TRPC1 promoted the proliferation, migration, and invasion of human esophageal squamous cell carcinoma cell line EC9706 . In contrast, overexpression of TRPC1 inhibited the proliferation, migration, and invasion of human esophageal squamous cell carcinoma cell line KYSE150 (<0.01), in a manner at least in part mediated through the AKT/p27 pathway.
TRPC1 inhibited the proliferation, migration, and invasion of EC9706 and KYSE150 cells, at least, in part mediated through the AKT/p27 pathway . The downregulation of TRPC1 may be one of the most important molecular events in the malignant progression of ESCC. TRPC1 could be a new candidate tumor suppressor gene and a new prognostic factor of ESCC.
在中国，超过90%的食管癌（EC）病例为食管鳞状细胞癌（ESCC）。ESCC是一种常见的恶性肿瘤，尽管综合治疗策略不断发展，但其预后仍较差，目前仍缺乏有效的预后因素。既往研究发现，瞬时受体电位阳离子通道蛋白1（TRPC1）的异常表达与多种肿瘤的增殖、侵袭、转移及分化密切相关。然而，TRPC1与ESCC之间的关系目前尚不清楚。本研究旨在阐明TRPC1的临床意义，并初步评估TRPC1调节ESCC细胞增殖、迁移和侵袭的分子机制。
采用免疫组织化学（IHC）法检测165例ESCC组织中TRPC1和Ki-67的表达。确定TRPC1表达与临床病理特征之间的相关性，并采用单因素和多因素分析来量化TRPC1表达对患者生存的影响。分别使用细胞计数试剂盒-8、划痕伤口愈合实验和Transwell实验来检测TRPC1对ESCC细胞增殖、迁移和侵袭的影响。
与正常食管黏膜（NEM；80.80%）和高级别上皮内瘤变（HGIEN；63.20%）相比，ESCC中TRPC1的阳性表达率显著降低（45.50%）（<0.001）。TRPC1表达率较高与低淋巴结转移（<0.001）、高分化（P = 0.232，P = 0.003）和低Ki-67（P = -0.492，<0.001）相关。我们进一步发现，TRPC1低表达与预后不良相关（无病生存期，DFS：95%CI = 0.545 - 0.845，P = 0.001；总生存期，OS：95%CI = 0.553 - 0.891，P = 0.004）。此外，我们发现TRPC1的下调促进了人食管鳞状细胞癌细胞系EC9706的增殖、迁移和侵袭。相反，TRPC1的过表达抑制了人食管鳞状细胞癌细胞系KYSE150的增殖、迁移和侵袭（<0.01），至少部分是通过AKT/p27途径介导的。
TRPC1至少部分通过AKT/p27途径抑制EC9706和KYSE150细胞的增殖、迁移和侵袭。TRPC1的下调可能是ESCC恶性进展中最重要的分子事件之一。TRPC1可能是一种新的候选肿瘤抑制基因和ESCC的新预后因素。
