METTL3 promotes oxaliplatin resistance of gastric cancer CD133+stem cells by promoting PARP1 mRNA stability

Oxaliplatin is the first-line regime for advanced gastric cancer treatment, while its resistance is a major problem that leads to the failure of clinical treatments. Tumor cell heterogeneity has been considered as one of the main causes for drug resistance in cancer. In this study, the mechanism of oxaliplatin resistance was investigated through in vitro human gastric cancer organoids and gastric cancer oxaliplatin-resistant cell lines and in vivo subcutaneous tumorigenicity experiments. The in vitro and in vivo results indicated that CD133+ stem cell-like cells are the main subpopulation and PARP1 is the central gene mediating oxaliplatin resistance in gastric cancer. It was found that PARP1 can effectively repair DNA damage caused by oxaliplatin by means of mediating the opening of base excision repair pathway, leading to the occurrence of drug resistance. The CD133+ stem cells also exhibited upregulated expression of N6-methyladenosine (m6A) mRNA and its writer METTL3 as showed by immunoprecipitation followed by sequencing and transcriptome analysis. METTTL3 enhances the stability of PARP1 by recruiting YTHDF1 to target the 3 '-untranslated Region (3 '-UTR) of PARP1 mRNA. The CD133+ tumor stem cells can regulate the stability and expression of m6A to PARP1 through METTL3, and thus exerting the PARP1-mediated DNA damage repair ability. Therefore, our study demonstrated that m6A Methyltransferase METTL3 facilitates oxaliplatin resistance in CD133+ gastric cancer stem cells by Promoting PARP1 mRNA stability which increases base excision repair pathway activity.

Automated summary

In this study, the researchers investigated the mechanism of oxaliplatin resistance in gastric cancer using in vitro human gastric cancer organoids and oxaliplatin-resistant cell lines, as well as in vivo tumorigenicity experiments. They found that CD133+ stem cell-like cells are the main subpopulation associated with resistance, and that the gene PARP1 plays a central role in mediating this resistance. The researchers discovered that PARP1 can effectively repair DNA damage caused by oxaliplatin by activating the base excision repair pathway, leading to the development of drug resistance. They also found that CD133+ cells exhibit increased expression of the mRNA modification N6-methyladenosine (m6A) and its writer METTL3, which enhances the stability of PARP1 and contributes to its DNA damage repair ability. Overall, this study demonstrates that m6A methyltransferase METTL3 promotes oxaliplatin resistance in CD133+ gastric cancer stem cells by increasing PARP1 mRNA stability and base excision repair activity.