A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression
A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression
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GRN 自分泌依赖性 FAM135B/AKT/mTOR 前馈环促进食管鳞状细胞癌进展
DOI：
10.1158/0008-5472.can-20-0912
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发表时间：
2021-02-15
期刊：
影响因子：
11.2
通讯作者：
Zhan, Qimin
中科院分区：
文献类型：
--
作者：
Dong, Dezuo;Zhang, Weimin;Zhan, Qimin
食管鳞状细胞癌（ESCC）是最常见、最致命的疾病之一。在我们之前的全面基因组学研究中，我们发现序列相似的家族135成员B （FAMI35B）是一个新的癌症相关基因，但其生物学功能和分子机制尚不清楚。在本研究中，我们发现FAM135B蛋白在ESCC组织中的表达水平明显高于癌前组织，并且FAM135B的高表达与较差的临床预后相关。FAM135B的异位表达促进了体外和体内ESCC细胞的增殖，可能是通过其与生长因子GRN的直接相互作用，从而与AKT/mTOR信号通路形成前馈回路。FAM135B和GRN均过表达的ESCC患者预后较差；多因素Cox模型分析显示FAMI35B和GRN的高表达是ESCC患者的独立预后因素。经4-硝基喹啉1-氧化物处理后，FAM135B转基因小鼠肿瘤负荷较野生型小鼠重，存活时间相对较短。此外，转基因小鼠血清GRN水平高于野生型小鼠，提示血清GRN水平可作为ESCC患者的诊断鉴别依据。这些发现提示FAM135B和GRN之间的相互作用在ESCC的进展调控中起关键作用，FAM135B和GRN可能是ESCC的潜在治疗靶点和预后因素。意义：这些发现探讨了FAM135B促进ESCC进展的机制，并为ESCC患者提供了新的潜在预后生物标志物和治疗靶点。
Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly diseases. In our previous comprehensive genomics study, we found that family with sequence similarity 135 member B (FAMI35B) was a novel cancer-related gene, yet its biological functions and molecular mechanisms remain unclear. In this study, we demonstrate that the protein levels of FAM135B are significantly higher in ESCC tissues than in precancerous tissues, and high expression of FAM135B correlates with poorer dinical prognosis. Ectopic expression of FAM135B promoted ESCC cell proliferation in vitro and in vivo, likely through its direct interaction with growth factor GRN, thus forming a feedforward loop with AKT/mTOR signaling. Patients with ESCC with overexpression of both FAM135B and GRN had worse prognosis; multivariate Cox model analysis indicated that high expression of both FAMI35B and GRN was an independent prognostic factor for patients with ESCC. FAM135B transgenic mice bore heavier tumor burden than wild-type mice and survived a relatively shorter lifespan after 4-nitroquinoline 1-oxide treatment. In addition, serum level of GRN in transgenic mice was higher than in wild-type mice, suggesting that serum GRN levels might provide diagnostic discrimination for patients with ESCC. These findings suggest that the interaction between FAM135B and GRN plays critical roles in the regulation of ESCC progression and both FAM135B and GRN might be potential therapeutic targets and prognostic factors in ESCC.Significance: These findings investigate the mechanisms of FAM135B in promoting ESCC progression and suggest new potential prognostic biomarkers and therapeutic targets in patients with ESCC.