融合基因CLDN18-ARHGAP26通过Rab7/脂噬途径介导弥漫型胃癌化疗耐药的机制研究

耐药是导致弥漫型胃癌化疗失败的重要原因，目前缺少有效干预措施。药物耐受持续细胞(Drug-Tolerant Persister, DTP)是肿瘤获得稳定耐药能力前的过渡状态细胞，抑制DTP形成有望阻断肿瘤化疗耐药。我们前期研究发现，融合基因CLDN18-ARHGAP26是弥漫型胃癌的特征性基因，能增强胃癌化疗耐药性。研究显示脂噬可参与肿瘤耐药中起重要作用。据此，我们推测该融合基因可能通过Rab7调控脂噬，从而介导弥漫型胃癌化疗耐药。本项目拟通过荷瘤鼠为研究模型，结合临床样本，阐明融合基因CLDN18-ARHGAP26通过脂噬通路调控DTP化疗耐药的具体机制，以证实上述假设。本项目可为克服胃癌耐药提供新思路。

Chemo-resistance is an important factor for the failure of chemotherapy in diffuse gastric cancer, but it lacks effective interventions currently. Drug-Tolerant Persister (DTP) is a small group of transitional-stated tumor cells before obtaining stable capability of chemo-resistance during the chemotherapy. Inhibiting the formation of the DTP is expected to block the chemo-resistant capability of tumor cell. Our previous study confirmed that the fusion gene CLDN18-ARHGAP26 significantly reduced the chemo-sensitivity of gastric cancer and promoted the formation of DTP; further study revealed that the fusion gene enhanced lipophagy of DTP and activated Rab7 protease. Lipophagy is illustrated to play a vital role in regulating chemo-resistance in cancer, and Rab7 involves in regulating lipophagy. Therefore, we presume that the fusion gene could regulate the chemo-resistant of DTP through lipophagy pathway via Rab7 in gastric cancer. Using CRISPR/CAS9, immunofluorescence co-localization and other technologies, with the DTP and mice as well as clinical tissue samples, we intend to clarify the specific molecular mechanism of the fusion gene CLDN18-ARHGAP26/Rab7/lipophagy signaling pathway regulating the chemo-resistance of DTP, so as to confirm the above presumption. Our study will provide new therapeutic evidence for solving the problem of chemo-resistance of gastric cancer.