Abstract
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.
Highlights
Gastric cancer (GC) is one of the most universal malignant tumors globally, especially in those lessdeveloped regions
ATXN2L upregulation in GC indicates adverse prognosis To find out the expression status of ATXN2L in GC, we analyzed GC data from The Cancer Genome Atlas dataset, which included 27 pairs of cancer and adjacent noncancerous tissue
ATXN2L contributed to GC recurrence and progression even under the treatment of oxaliplatin
Summary
Gastric cancer (GC) is one of the most universal malignant tumors globally, especially in those lessdeveloped regions. ATXN2L is a paralog of Ataxin-2 (ATXN2) but without abnormal polyQ expended track, which is conserved in most of the ATXNs and drives the pathogenesis of neurodegeneration. This suggests that they might share some especial characteristics. It is already known that EGFR signaling activation contributes to intrinsic oxaliplatin resistance[10,11], while anti-EGFR treatment can reverse acquired oxaliplatin resistance[12]. Apart from these limited clues, the function of ATXN2L in cancer remained greatly unknown. Whether ATXN2L is associated with oxaliplatin resistance or EGFR signaling was unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
