TMEM231介导POSTN诱导PFKFB2增强胃癌细胞Warburg效应促进化疗抵抗的机制

The role of TMEM231, a transmembrane protein, was not studied in tumor. Our recent results showed that TMEM231 expression was associated with chemoresistance in patients with gastric cancer. We noticed that TMEM231 could activate the PI3K/AKT/NF-κB signaling pathway, up-regulate PFKFB2, and enhance the Warburg effect. POSTN, a secretory protein of extracellular matrix, plays an important role in chemoresistance. POSTN could also activate the PI3K/AKT/NF-κB signaling pathway, up-regulate PFKFB2, and enhance the Warburg effect. Co-IP showed TMEM231 and POSTN had mutually combination. ChIP showed that NF-κB p65 could bind to the promoter region of PFKFB2. Therefore, the follow-up studies need to clear: TMEM231, as a candidate oncogene, mediates POSTN to activate the PI3K/AKT signaling pathway, and then induce NF-κB p65 to stimulate the transcription of PFKFB2, and finally enhance Warburg effect and promote chemoresistance. The study will elucidate the key role of TMEM231 in chemoresistance and further clarify the regulatory mechanism that POSTN involves in chemoresistance of gastric cancer cells through interacting with TMEM231.

TMEM231为跨膜蛋白，在肿瘤中未有研究。我们前期发现TMEM231表达与胃癌化疗抵抗正向相关。机制初步显示TMEM231表达能激活PI3K/AKT/NF-κB信号通路，上调PFKFB2，增强Warburg效应。POSTN为基质分泌性蛋白，与化疗抵抗密切相关，机制分析发现同样激活PI3K/AKT/NF-κB通路，上调PFKFB2，增强Warburg效应。Co-IP发现TMEM231和POSTN存在相互结合。ChIP初步显示NF-κB p65可与PFKFB2启动子结合。因此后续研究需明确：TMEM231作为候选癌基因，介导POSTN激活PI3K/AKT通路，进而诱导NF-κB p65转录刺激PFKFB2表达，从而增强Warburg效应促进化疗抵抗。该项目顺利完成不但能阐明TMEM231在化疗抵抗中的作用，同时进一步明确POSTN通过TMEM231相互作用参与胃癌细胞化疗抵抗的重要调控机制。

胃癌是世界范围内一种常见的恶性肿瘤，也是引起肿瘤死亡的主要原因之一。手术切除和化疗是目前进展期胃癌治疗的主要手段。但是化疗对不同患者治疗疗效的差异显著，常常出现相同分期的患者进行相同化疗方案，化疗疗效不同的情况，说明很多胃癌患者存在化疗抵抗，而且当前分期系统不能准确筛选化疗敏感的病人。加强胃癌化疗抵抗的机制研究，寻找可靠的预测指标和有效的治疗靶点，对于提高进展期胃癌缓解率，降低死亡率具有重要的科学意义。本研究我们分析了POSTN在228 例胃癌患者的石蜡组织标本中的表达，显示POSTN 低表达的胃癌患者化疗生存获益显著，而POSTN高表达的患者化疗无明显生存获益，表明POSTN高表达可能引起胃癌的化疗抵抗。进一步阐明了POSTN激活PI3K/AKT/NF-κB信号通路，上调PFKFB2，增强胃癌细胞的Warburg效应，进而促进化疗抵抗的调控机制。对该调控机制的阐明一定程度上解释了POSTN促进胃癌细胞化疗抵抗的分子机制，为胃癌临床治疗提供新的靶点和思路，为研制新型个体化治疗策略提供理论基础。