Hsa_circ_0000437 promotes pathogenesis of gastric cancer and lymph node metastasis
Hsa_circ_0000437 promotes pathogenesis of gastric cancer and lymph node metastasis
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Hsa_circ_0000437促进胃癌发病及淋巴结转移
DOI：
10.1038/s41388-022-02449-w
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发表时间：
2022-09
期刊：
影响因子：
8
通讯作者：
Shaoqing Ju
中科院分区：
文献类型：
--
作者：
Xianjuan Shen;Shan Kong;Shuo Ma;Lei Shen;Ming zheng;Shiyi Qin;Jing Qi;Qiuhong Wang;Xiaopeng Cui;Shaoqing Ju
具有不同转移潜能和微环境的胃癌（GC）细胞之间的细胞通讯以及由此产生的癌症进展尚未完全了解。已知环状RNA（circRNA）和外泌体circRNA在GC的发生和发展中起着极其重要的调节作用。在这里，我们揭示了胃癌和癌旁组织之间冠状蛋白样肌动蛋白结合蛋白1C（CORO 1C）衍生的circRNA hsa_circ_0000437的显著差异。Hsa_circ_0000437通过靶向SRSF 3和抑制PDCD 4调节胃癌细胞增殖、侵袭、迁移和凋亡。hsa_circ_0000437的异位表达显著促进裸鼠体内肿瘤生长。此外，功能获得和功能丧失实验均表明，hsa_circ_0000437在体外促进人淋巴管内皮细胞（HLEC）的侵袭、迁移和管形成，并且在体内在腘淋巴结转移（LNM）模型中也促进淋巴管生成和淋巴结转移（LNM），当其富含GC分泌的外泌体并转移到HLEC中时。机制上，外泌体hsa_circ_0000437通过不依赖于VEGF-C的HSPA 2-ERK信号通路诱导LNM。临床数据显示，外泌体hsa_circ_0000437在GC患者血清中富集，其与LNM相关。总之，这些发现强调了hsa_circ_0000437作为LNM GC患者结局生物标志物的潜在作用，这可能为GC治疗提供新的靶点。
Cellular communication between gastric cancer (GC) cells with different metastatic potentials and microenvironments and resultant cancer progression is not fully understood. Circular RNAs (circRNAs) and exosomal circRNAs are known to play extremely important regulatory roles in GC occurrence and progression. Here, we revealed significant differences in coronin-like actin-binding protein 1C (CORO1C) derived circRNA hsa_circ_0000437 between GC and para-cancer tissues. Hsa_circ_0000437 regulated GC cell proliferation, invasion, migration and apoptosis by targeting Ser/Arg-rich splicing factor 3 (SRSF3) and inhibiting programmed cell death 4 (PDCD4). The ectopic expression of hsa_circ_0000437 dramatically promoted tumor growth in nude mice in vivo. Furthermore, both gain-of-function and loss-of-function experiments demonstrated that hsa_circ_0000437 promoted human lymphatic endothelial cells (HLECs) invasion, migration, and tube formation in vitro and also promoted lymphangiogenesis and lymph node metastasis (LNM) in popliteal LNM model in vivo, when it was enriched in GC-secreted exosomes and transferred into HLECs. Mechanistically, exosomal hsa_circ_0000437 induced LNM via HSPA2-ERK signaling pathway independent of VEGF-C. Clinical data showed that exosomal hsa_circ_0000437 was enriched in the serum of GC patients, which was associated with LNM. In summary, these findings highlight the potential role of hsa_circ_0000437 as an outcome biomarker in GC patients with LNM, which may provide a novel target for GC therapy.
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