Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Cell Death Dis. 2019 Feb 20;10(3):173. doi: 10.1038/s41419-019-1362-2.
For gastric cancer (GC) control, metastasis and chemoresistance are the major challenges, accompanied with various stresses. Ataxin-2-like (ATXN2L) was discovered as a novel regulator of stress granules, yet its function in cancers remained unknown. Hence, we wanted to explore the functions of ATXN2L to see whether it participates in stress-related cancer malignant activities. Clinical follow-up was performed to see the impact of ATXN2L on GC patient survival. As a result, ATXN2L expression was upregulated in GC tissue and indicated adverse prognosis for overall survival and recurrence. In GC cells, ATXN2L expression was knocked down and functional experiments were performed. ATXN2L promoted GC cell migration and invasion via epithelial to mesenchymal transition, yet no influence on proliferation was detected by ATXN2L interference. When adding the chemotherapeutic agent oxaliplatin to induce stress, silencing ATXN2L sensitized GC cells to oxaliplatin. Interestingly, oxaliplatin was found to in turn promote ATXN2L expression and stress granule assembly. Then, two acquired oxaliplatin-resistant strains were generated by long-term oxaliplatin induction. The oxaliplatin-resistant strains presented with elevated ATXN2L levels, while silencing ATXN2L in the strains reversed the oxaliplatin resistance by increasing reactive oxygen species production and apoptosis. These results suggested that ATXN2L was responsible for not only intrinsic but also acquired oxaliplatin chemoresistance. Finally, ATXN2L-related signaling was screened using bioinformatic methods, and epidermal growth factor (EGF) was verified to promote ATXN2L expression via PI3K/Akt signaling activation. Blocking EGFR/ATXN2L signaling reversed GC cell oxaliplatin resistance and inhibited migration. In conclusion, ATXN2L promotes cell invasiveness and oxaliplatin resistance and can be upregulated by EGF via PI3K/Akt signaling. ATXN2L may be an indicator and therapeutic target in GC, especially for oxaliplatin-based chemotherapy.
为了控制胃癌（GC），转移和化疗耐药是主要挑战，同时伴随着各种应激。Ataxin-2 样（ATXN2L）被发现是应激颗粒的新型调节因子，但它在癌症中的功能尚不清楚。因此，我们想要探索 ATXN2L 的功能，以观察它是否参与与应激相关的癌症恶性活动。进行临床随访以观察 ATXN2L 对 GC 患者生存的影响。结果表明，ATXN2L 在 GC 组织中表达上调，并预示着总生存和复发的不良预后。在 GC 细胞中，敲低 ATXN2L 并进行功能实验。ATXN2L 通过上皮间质转化促进 GC 细胞迁移和侵袭，但 ATXN2L 干扰未检测到对增殖的影响。当添加化疗药物奥沙利铂诱导应激时，沉默 ATXN2L 使 GC 细胞对奥沙利铂敏感。有趣的是，发现奥沙利铂反过来促进 ATXN2L 表达和应激颗粒组装。然后，通过长期奥沙利铂诱导生成了两个获得奥沙利铂耐药的株系。奥沙利铂耐药株系的 ATXN2L 水平升高，而在株系中沉默 ATXN2L 通过增加活性氧产生和细胞凋亡逆转了奥沙利铂耐药性。这些结果表明，ATXN2L 不仅负责内在的而且负责获得性奥沙利铂化疗耐药性。最后，使用生物信息学方法筛选 ATXN2L 相关信号，验证表皮生长因子（EGF）通过 PI3K/Akt 信号激活促进 ATXN2L 表达。阻断 EGFR/ATXN2L 信号逆转 GC 细胞奥沙利铂耐药性并抑制迁移。总之，ATXN2L 促进细胞侵袭性和奥沙利铂耐药性，并且可以通过 PI3K/Akt 信号被 EGF 上调。ATXN2L 可能是 GC 的标志物和治疗靶点，特别是对于基于奥沙利铂的化疗。
