Abstract
GNB2L1 and its O-GlcNAcylation has been reported to play roles in gastric cancer metastasis. However, the roles of GNB2L1 in chemoresistance of gastric cancer has never been determined. In the present study, we found that GNB2L1 was downregulated in chemoresistant patients of gastric cancer, and observed the decrease of GNB2L1 in protein levels instead of mRNA levels in different chemoresistant gastric cancer cell lines. Further we proved that this downregulation of GNB2L1 was resulted from its elevated O-GlcNAcylation catalyzed by OGT in both cell lines and patients. Next, we investigate the function of GNB2L1 and its O-GlcNAcylation on gastric cancer metastasis during chemoresistance, and confirmed Ser124 as the major O-GlcNAcylation site on GNB2L1 that regulated its function on metastasis. Furthermore, our data demonstrated that GNB2L1 modulated EMT via regulating the translation of EMT-related proteins in the process of chemoresistance. In summary, this study indicated that GNB2L1 and its O-GlcNAcylation regulated metastasis via modulating the translation of EMT-related proteins in the chemoresistance of gastric cancer.
Highlights
Gastric cancer ranks the fifth most common type of cancer and the third leading cause of cancer-related mortality worldwide [1]
We found that GNB2L1 was downregulated in the chemoresistance of gastric cancer, while its O-GlcNAcylation was elevated by OGT at meantime
After completion of the chemotherapy, the responses of the patients were assessed by criteria defined by the World Health Organization, which defines the responses as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD)
Summary
Gastric cancer ranks the fifth most common type of cancer and the third leading cause of cancer-related mortality worldwide [1]. Despite the improvements in screening activities and clinical treatments reduced the incidence of gastric cancer, the overall outcome has not significantly improved over the last few decades [2]. Metastasis and recurrence of gastric cancer is closely related with its poor outcome [3, 4]. Chemotherapy, which is commonly used to reduce the risk of recurrence and metastasis in patients with localized disease after surgery, can significantly improve the outcome [5, 6]. The overall benefits of chemotherapy are largely limited due to drug resistance during treatment, especially multidrug resistance (MDR) [6].
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