Zuo Jin Wan Reverses the Resistance of Colorectal Cancer to Oxaliplatin by Regulating the MALAT1/miR-200s/JNK Signaling Pathway

Abstract

Background. Oxaliplatin (L-OHP) is a common chemotherapy drug used in the treatment of colorectal cancer (CRC). Our previous work showed that Zuo Jin Wan (ZJW), a traditional Chinese medicine prescription, could improve sensitivity to L-OHP in the treatment of CRC, but the detailed mechanism is not clear. In previous mechanistic studies, we found that the miR-200s expression in CRC is associated with L-OHP sensitivity through regulation of MDR1/p-gp and the downstream c-JunN-terminal kinase (JNK) signaling pathway. Moreover, lncRNA-MALAT1 offers great potential in the regulation of drug resistance by interacting with miR-200s. Therefore, in this work, we explored whether ZJW could reverse L-OHP resistance in CRC by regulating MALAT1, miR-200s, and the downstream signaling pathway. Methods. Cell Counting Kit-8 and flow cytometry were used to detect the effects of ZJW combined with L-OHP on chemotherapy tolerance and cell apoptosis of HCT116/L-OHP cells. Western blotting and quantitative real-time PCR (qRT-PCR) were used to detect the activation of the JNK signaling pathway and the protein and mRNA expression levels of the drug resistance-related MDR1/ABCB1 gene in HCT116/L-OHP cells treated with ZJW. The binding sites of MALAT1 and miR-200s were predicted by bioinformatics tools and confirmed by qRT-PCR. qRT-PCR was used to detect the expression of miR-200s and MALAT1 in HCT116/L-OHP cells treated with ZJW. A xenograft model of CRC in nude mice was established to observe the effect of ZJW combined with L-OHP on the growth of subcutaneously transplanted tumors. Apoptosis in tumor cells was detected by TUNEL staining. The activation of the JNK signaling pathway and the expression of drug resistance-related proteins were detected by immunohistochemistry and immunofluorescence. qRT-PCR was used to detect the expression of miR-200s and the MALAT1 gene in the tumors. Results. Our study showed that ZJW could significantly decrease the proliferation and promote apoptosis of HCT116/L-OHP cells treated with L-OHP. We further proved that ZJW could reverse the drug resistance of HCT116/L-OHP cells by reducing MALAT1, indirectly upregulating miR-200s, alleviating the activation of the JNK signaling axis, and downregulating the expression of resistance proteins such as MDR1/ABCB1 and ABCG2. ZJW combined with L-OHP inhibited the growth of subcutaneously transplanted tumors and induced apoptosis in nude mice. ZJW reduced the expression of MALAT1 and upregulated the expression of miR-200s in transplanted tumors. In addition, ZJW also alleviated the activation of the JNK signaling pathway while reducing the expression of MDR1/ABCB1 and ABCG2. Conclusions. Our study identified that MALAT1 promotes colorectal cancer resistance to oxaliplatin by reducing the miR-200s expression. ZJW may reverse chemoresistance by inhibiting the expression of MALAT1 and regulating the miR-200s/JNK pathway, providing an experimental basis for the clinical application of ZJW in relieving chemotherapy resistance.

Biological landscape and nanostructural view in development and reversal of oxaliplatin resistance in colorectal cancer

“…Noteworthy, anti-tumor compounds are able to regulate expression level of non-coding RNAs in affecting OXA sensitivity of CRC cells. Zuo Jin Wan increases expression level of miR-200s via MALAT1 down-regulate to suppress JNK signaling in apoptosis induction, proliferation inhibition and OXA sensitivity in CRC cells [ 247 ]. Resveratrol is another compound that has been used in disease and cancer therapy, and nano-scale delivery systems have been employed in increasing its bioavailability and therapeutic index.…”

The functions and mechanisms of long non-coding RNA in colorectal cancer

“…In Wei’s study on the traditional Chinese medicine Zuojin Wan, it was found that MALAT1 promotes resistance to oxaliplatin in CRC by decreasing the expression of miR-200s. Zuojin Wan may reverse chemotherapy resistance by inhibiting the expression of MALAT1 and regulating the miR-200s/JNK pathway ( 158 ). Cai et al.…”

Association of Genetic Polymorphism of ABCG2 Gene and the Occurrence of Oxaliplatin-Induced Peripheral Neuropathy in Patients with Colorectal Cancer

“…Further, it should be highlighted that the majority of prior pharmacogenomics research, including our work, has concentrated on a single candidate gene, whose clinical importance is restricted and may not be sufficient to predict the frequency of severe oxaliplatin peripheral neuropathy and oxaliplatin resistance [22,24,25].…”