Xiangjun Meng

The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway, a pivotal immune checkpoint, enables tumor immune evasion, and its blockade is fundamental to cancer immunotherapy. The development of small-molecule agents targeting the PD-1/PD-L1 pathway offers a promising strategy for enhancing antitumor immunity. In this study, we screened an in-house compound library using RKO cells to discover novel PD-L1 downregulators. MS1-96 was identified as a potent PD-L1 degrader that promotes lysosome-dependent PD-L1 degradation. Furthermore, MS1-96 effectively reduced PD-L1 protein levels across multiple colorectal cancer (CRC) cell lines. By disrupting the PD-1/PD-L1 pathway, MS1-96 enhances CD8⁺ T cell-mediated killing of carcinoma cells and exerts dose-dependent antitumor effects in C57BL/6 mice bearing MC38 CRC xenografts, resulting in significant tumor growth inhibition after oral administration for 10 d (100, 200, or 400 mg·kg⁻¹·d⁻¹). Mechanistic studies revealed that Huntingtin interacting protein 1-related (HIP1R) plays an indispensable role in MS1-96-driven PD-L1 degradation, and HIP1R knockdown abolishes MS1-96’s ability to degrade PD-L1. MS1-96 directly binds to PD-L1 with a K_D of 2.58 μM and enhances the interaction between HIP1R and PD-L1, thereby altering the intracellular trafficking of PD-L1 within clathrin-coated vesicles. This leads to reduced transport of PD-L1 to recycling endosomes and increased delivery to late endosomes and lysosomes for degradation. Furthermore, MS1-96 induces abnormal N-glycosylation of PD-L1, destabilizing the protein and hastening its lysosome-mediated degradation. Moreover, MS1-96 effectively enhances the antitumor efficacy of PD-1 antibodies in MC38 CRC models. These findings indicate that MS1-96 offers a potential strategy for advancing tumor immunotherapy.

Background: The European Society of Gastrointestinal Endoscopy recommends 4L Polyethylene Glycol (PEG) as the standard regimen for bowel preparation (BP). The current study compared 3L and 4L PEG with regard to their effectiveness, tolerability, and safety among Chinese patients to identify the best bowel cleansing method for this population. Methods: The study employed a prospective, observer-blinded, randomized and controlled de-sign in a high-volume endoscopic center. Consecutive patients undergoing colonoscopy were randomly assigned (1:1) to the 3L-PEG or 4L-PEG group. The quality of bowel cleansing, procedure time, adenoma detection rate (ADR), patient tolerance, and adverse events were compared. Results: A total of 330 patients were included in the study. After exclusions, 160 cases in the 3L-PEG group and 158 cases in the 4L-PEG group were included in the final analy-sis. The quality of bowel cleansing (Boston Bowel Preparation Scale) for both the whole intestine and each segment had no significant differences between the groups (P > 0.05). No significant differences were found with regard to procedure time or ADR. The incidences of adverse events such as nausea (P = 0.001), vomiting (P = 0.002), and bloating (P < 0.001) were lower in the 3L-PEG group. Moreover, there was a higher rate of satisfaction in the 3L-PEG group than in the 4L-PEG group (P = 0.009). Conclusions: 3L-PEG bowel cleansing represents an optimal alternative to a 4L-PEG preparation, showing similar efficacy and superior levels of satisfaction, acceptability, and safety among users. We recommend 3L PEG as a routine regimen in the clinical setting for Chinese patients. (ClinicalTrials.gov registration number: NCT03356015, registered in 29 November, 2017, https://www.clinicaltrials.gov/ct2/show/ NCT03356015).

Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960’s. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes. Then, they discovered that these organo-ruthenium/osmium complexes could act independently of DNA damage and bypass the requirement for the tumor suppressor gene TP53 to induce the endoplasmic reticulum (ER) stress pathway, which is an original cell death pathway. They showed that other types of ruthenium complexes—as well complexes with other metals (osmium, iron, platinum)—can induce this pathway as well. They also demonstrated that ruthenium complexes accumulate in the ER after entering the cell using passive and active mechanisms. These particular physico-chemical properties of the organometallic complexes designed by Dr. Pfeffer contribute to their ability to reduce tumor growth and angiogenesis. Taken together, the pioneering work of Dr. Michel Pfeffer over his career provides us with a legacy that we have yet to fully embrace.

New-onset diabetes mellitus has a rough correlation with pancreatic cancer (PaC), but the underlying mechanism remains unclear. This study aimed to explore the exosomal microRNAs and their potential role in PaC-induced β-cell dysfunction. The pancreatic β cells were treated with isolated exosomes from PaC cell lines, SW1990 and BxPC-3, before measuring the glucose-stimulated insulin secretion (GSIS), validating that SW1990 and BxPC-3 might disrupt GSIS of both β cell line MIN6 and primary mouse pancreatic islets. The difference in expression profiles between exosomes and exosome-free medium of PaC cell lines was further defined, revealing that miR-19a secreted by PaC cells might be an important signaling molecule in this process. Furthermore, adenylyl cyclase 1 (Adcy1) and exchange protein directly activated by cAMP 2 (Epac2) were verified as the direct targets of exogenous miR-19a, which was involved in insulin secretion. These results indicated that exosomes might be an important mediator in the pathogenesis of PaC-DM, and miR-19a might be the effector molecule. The findings shed light on the pathogenesis of PaC-DM.

Background: Chemoresistance remains a critical event that accounts for colorectal cancer (CRC) lethality. The aim of this study is to explore the ability of dichloroacetate (DCA) to increase chemosensitivity in CRC and the molecular mechanisms involved. Methods: The effects of combination treatment of DCA and oxaliplatin (L-OHP) were analysed both in vitro and in vivo. The DCA-responsive proteins in AMPK pathway were enriched using proteomic profiling technology. The effect of DCA on CAB39–AMPK signal pathway was analysed. In addition, miRNA expression profiles after DCA treatment were determined. The DCA-responsive miRNAs that target CAB39 were assayed. Alterations of CAB39 and miR-107 expression were performed both in vitro and on xenograft models to identify miR-107 that targets CAB39–AMPK–mTOR signalling pathway. Results: DCA increased L-OHP chemosensitivity both in vivo and in vitro. DCA could upregulate CAB39 expression, which activates the AMPK/mTOR signalling pathway. CAB39 was confirmed to be a direct target of miR-107 regulated by DCA. Alterations of miR-107 expression were correlated with chemoresistance development in CRC both in vitro and in vivo. Conclusion: These findings suggest that the miR-107 induces chemoresistance through CAB39–AMPK–mTOR pathway in CRC cells, thus providing a promising target for overcoming chemoresistance in CRC.

Tribbles homolog 3 (TRB3), a type of pseudokinase that contains a consensus serine/threonine kinase catalytic core structure, is upregulated in hepatocellular carcinoma. However, the effect of TRB3 expression in hepatocellular carcinoma and the molecular mechanisms underlying TRB3‑mediated effects on tumorigenesis in hepatocellular carcinoma have not been fully elucidated. The present study focused on the effect of TRB3 expression in MHCC97H hepatocellular carcinoma cells and investigated the underlying molecular mechanisms in MHCC97H cells. In the present study, it was revealed that TRB3 was significantly overexpressed in the MHCC97H hepatocellular carcinoma cell compared with L‑02 normal hepatic cells. Under endoplasmic reticulum (ER) stress induced by thapsigargin and tunicamycin, the levels of TRB3, CCAAT/enhancer binding protein homologous protein (CHOP), protein kinase B (AKT) and phosphorylated (p)AKT expression were upregulated. Furthermore, when the expression of TRB3 was silenced by short hairpin (sh)RNA, the survival of MHCC97H hepatocellular carcinoma cells was increased. Notably, following transduction with lentiviral containing TRB3‑shRNA, cell survival also increased after treatment with chemotherapy drug cisplatin. The present study demonstrated that knockdown of CHOP by shRNA was able to reduce TRB3 expression, and the knockdown of TRB3 markedly increased the level of pAKT. TRB3 was overexpressed in MHCC97H hepatocellular carcinoma cells, particularly under endoplasmic reticulum stress. Knockdown of TRB3 was able to increase cell survival. Therefore, TRB3 expression may induce apoptosis and reverse resistance to chemotherapy in MHCC97H hepatic carcinoma cells. The present study suggests that TRB3 is a key molecule that mediates the crosstalk between ER stress and AKT signal pathways. Furthermore, the present study may provide further insight into the cancer biology of hepatocellular carcinoma and the development of anticancer drugs targeting the ER stress and AKT signaling pathways.