Colorectal cancer (CRC) has a high mortality rate and poor prognosis. Despite chemotherapeutic agents such as cisplatin, which has achieved a better prognosis and survival rate against cancer, drug resistance leads to significant challenges. Accumulating evidence suggests that YTHDF1, the N6-methyladenosine (m6A) “reader,” is an important regulator in tumor progresses. Herein, we report that YTHDF1 was significantly upregulated in human colon tumors and cell lines. Overexpression of YTHDF1 decreased the cisplatin sensitivity of colon cancer cells. From the established cisplatin-resistant CRC cell line (LoVo CDDP R), we detected that YTHDF1 was significantly upregulated in cisplatin-resistant CRC cells. Intriguingly, RNA sequencing (RNA-seq) results revealed that glutamine metabolism enzymes were clearly upregulated in LoVo CDDP R cells. Glutamine uptake, that is, glutaminase (GLS) activity, was upregulated in LoVo CDDP R cells. Furthermore, bioinformatics analysis indicated that the 3′ UTR of GLS1 contained a putative binding motif of YTHDF1, and an interaction was further validated by a protein-RNA interaction assay (RNA immunoprecipitation [RIP]). Furthermore, we demonstrated that YTHDF1 promoted protein synthesis of GLS1. Inhibiting GLS1 effectively synergizes with cisplatin to induce colon cancer cell death. Finally, that YTHDF1 mediated cisplatin through the GLS1-glutamine metabolism axis was validated by an in vivo xenograft mouse model. In summary, our study reveals a new mechanism for YTHDF1-promoted cisplatin resistance, contributing to overcoming chemoresistant colon cancers.

Background: Colorectal cancer (CRC) remains the most common gastrointestinal cancer and a leading cause of cancer deaths worldwide, with most showing pathologies indicating the malignant transformation of early stage intestinal stem cells. The long non-coding RNAMeg3, which functions as a tumor suppressor, has been reported to be abnormal in multiple tumorigenesis events; however, the underlying mechanism by whichMeg3contributes to the malignant proliferation of colonic stem cells remains unclear.Methods: We analyzed the expression levels ofMeg3,miR-708, and SOCS3 in samples fromApcloss-of-function (Apc^min) mice and patients with CRC, particularly in colonic crypt cells.Apc^minmice and AMO/DSS-induced mice model (in vivo) and organoid culture system (in vitro) were used to explore the effect of theMeg3/miR-708/SOCS3 axis on tumorigenesis in the colon. In vitro, we performed RNApull-down, RNA immunoprecipitation, and luciferase reporter assays using DLD1 and RKO cell lines.Findings: TheMeg3/miR-708/SOCS3 signaling axis plays a critical role in the early stage of CRC development. Our data showedMeg3levels negatively correlate withmiR-708levels both in clinical samples and in theApc^minmouse model, which indicated thatMeg3acts as a competitive endogenous RNA (ceRNA) ofmiR-708. Then,miR-708served as an oncogene, inducing neoplasia in bothApc^minmice and cultured colonic organoids. Put together,miR-708appears to promote malignant proliferation of colonic stem cells by targeting SOCS3/STAT3 signaling.Interpretation: These data revealed thatMeg3spongesmiR-708to inhibit CRC development via SOCS3-mediated repression of the malignant proliferation of colonic stem cells. TheMeg3/miR-708/SOCS3 signaling axis provides potential targets for the diagnosis and treatment of CRC, particularly early stage CRC.

In recent years, the incidences and mortalities from colorectal cancer (CRC) have been increasing; therefore, there is an urgent need to discover newer drugs that enhance drug sensitivity and reverse drug tolerance in CRC treatment. With this view, the current study focuses on understanding the mechanism of CRC chemoresistance to the drug as well as exploring the potential of different traditional Chinese medicine (TCM) in restoring the sensitivity of CRC to chemotherapeutic drugs. Moreover, the mechanism involved in restoring sensitivity, such as by acting on the target of traditional chemical drugs, assisting drug activation, increasing intracellular accumulation of anticancer drugs, improving tumor microenvironment, relieving immunosuppression, and erasing reversible modification like methylation, have been thoroughly discussed. Furthermore, the effect of TCM along with anticancer drugs in reducing toxicity, increasing efficiency, mediating new ways of cell death, and effectively blocking the drug resistance mechanism has been studied. We aimed to explore the potential of TCM as a sensitizer of anti-CRC drugs for the development of a new natural, less-toxic, and highly effective sensitizer to CRC chemoresistance.

Underwater endoscopic mucosal resection (UEMR) of colorectal lesions is emerging as an alternative method to conventional endoscopic mucosal resection (EMR); however, it is still controversial whether there is a difference in the effectiveness between UEMR and EMR. To evaluate the effectiveness and safety of UEMR in the treatment of colorectal polyps. Clinical studies comparing the effectiveness or safety of UEMR in the treatment of colorectal polyps were searched in medical databases, including PubMed, Embase, Cochrane Library, CNKI, and Wanfang Data, monographs, theses, and papers presented at conferences. Statistical analyses were performed using Revman 5.3 software. Seven non-randomized controlled trials and one randomized controlled trial met the inclusion criteria. In total, 1382 patients (1511 polyps) were included in the study, including 722 who received UEMR and 789 who received EMR. In the UEMR and EMR groups, the en bloc resection rates were 85.87% and 73.89%, respectively, with a relative risk (RR) value of 1.14 (95% confidence interval [CI]: 1.01-1.30; P < 0.05). In the sub-group analysis, the en bloc resection rate showed no statistically significant difference between the EMR and UEMR groups for polyps less than 20 mm in diameter. However, a statistically significant difference was found between the EMR and UEMR groups for polyps equal to or greater than 20 mm in diameter. The post-endoscopic resection recurrence rates at 3-6 mo of the UEMR and EMR groups were 3.26% and 15.17%, respectively, with an RR value of 0.27 (95%CI: 0.09-0.83; P < 0.05). The post-endoscopic resection recurrence rates of UEMR and EMR at 12 mo were 6.25% and 14.40%, respectively, with an RR value of 0.43 (95%CI: 0.20-0.92; P < 0.05). Additionally, the incidence of adverse events was 8.17% and 6.21%, respectively, with an RR value of 1.07 (95%CI: 0.50-2.30; P > 0.05). UEMR is an effective technique for colorectal polyps and appears to have some advantages over EMR, particularly with regard to some treatment outcomes.