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Bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers that play a critical role in oncogenesis by controlling the expression of oncogenes such as c-Myc. Targeting BET family proteins has recently emerged as a promising anticancer strategy. However, the molecular mechanisms by which cancer cells respond to BET inhibition are not well understood. In this study, we found that inducing the degradation of BET proteins by the proteolysis targeting chimeras (PROTAC) approach potently suppressed the growth of colorectal cancer (CRC) including patient-derived tumors. Mechanistically, BET degradation transcriptionally activates Death Receptor 5 (DR5) to trigger immunogenic cell death (ICD) in CRC cells. Enhanced DR5 induction further sensitizes CRC cells with a mutation in Speckle-type POZ protein (SPOP). Furthermore, DR5 is indispensable for a striking antitumor effect of combining BET degradation and anti-PD-1 antibody, which was well tolerated in mice and almost eradicated syngeneic tumors. Our results demonstrate that BET degradation triggers DR5-mediated ICD to potently suppress CRC and potentiate immune checkpoint blockade. These results provide a rationale, mechanistic insights, and potential biomarkers for developing a precision CRC therapy by inducing BET protein degradation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Stage III colorectal cancer (CRC) patients experience varying degrees of prognosis even if receiving standard therapeutic regimes. Intravascular emboli (IVE), a type of vascular invasion, impacts the clinical outcome in CRC. In this study, we confirmed the role of IVE in predicting the prognosis of stage III CRC patients and characterized the tumor microenvironment (TME) of CRC with IVE., Methods: Data from 220 consecutive patients (cohort 1) with stage III CRC undergoing radical surgery was collected retrospectively between January 2009 to December 2014. According to the presence of IVE, which was confirmed by two independent pathologists, patients were classified into two groups. Univariate and multivariate Cox regression analyses were performed to evaluate the relation of IVE presence to patients' prognosis. The association between IVE and clinicopathological factors was also analyzed. Furthermore, differentially expressed genes (DEGs) and gene set enrichment analyses (GSEA) were performed to describe features of the TME based on microarray data consisting of 6 patients. Tumor tissues from a separate cohort of 73 patients with stage III CRC (cohort 2) collected between June 2014 and December 2015 were used to analyze tumor-infiltrating lymphocyte (TIL) by immunohistochemistry (IHC) staining., Results: IVE was observed in 126 (57.3%) patients and could serve as an unfavorable independent prognostic predictor (P < 0.001) as well as lymph node metastasis (P < 0.05) and tumor location (P < 0.05). Additionally, patients with IVE had a higher neutrophil percentage (P = 0.002) and lower lymphocyte percentage (P = 0.002) relative to those without IVE. CRC with IVE had a significantly different profile of DEGs compared to CRC without IVE, and GSEA showed chronic inflammatory and immunosuppressive TME may promote IVE development. In cohort 2, tumors with IVE had fewer CD3 + TILs in the stromal region, as well as fewer CD8 + TILs in both stromal and tumoral regions relative to those without IVE., Conclusion: IVE, which was related closely to a chronic inflammatory and immunosuppressive TME, forecasted a worse prognosis of stage III CRC patients and may be taken into consideration when a therapeutic strategy is decided upon.

Intrinsic and acquired resistance to targeted therapies is a significant clinical problem in cancer. We previously showed that resistance to regorafenib, a multi-kinase inhibitor for treating colorectal cancer (CRC) patients, can be caused by mutations in the tumor suppressor FBW7 , which block degradation of the pro-survival Bcl-2 family protein Mcl-1. We tested if Mcl-1 inhibition can be used to develop a precision combination therapy for overcoming regorafenib resistance., Methods: Small-molecule Mcl-1 inhibitors were tested on CRC cells with knock-in (KI) of a non-degradable Mcl-1. Effects of Mcl-1 inhibitors on regorafenib sensitivity were determined in FBW7 -mutant and -wild-type (WT) CRC cells and tumors, and in those with acquired regorafenib resistance due to enriched FBW7 mutations. Furthermore, translational potential was explored by establishing and analyzing FBW7 -mutant and -WT patient-derived organoid (PDO) and xenograft (PDX) tumor models., Results: We found that highly potent and specific Mcl-1 inhibitors such as S63845 overcame regorafenib resistance by restoring apoptosis in multiple regorafenib-resistant CRC models. Mcl-1 inhibition re-sensitized CRC tumors with intrinsic and acquired regorafenib resistance in vitro and in vivo, including those with FBW7 mutations. Importantly, Mcl-1 inhibition also sensitized FBW7 -mutant PDO and PDX models to regorafenib. In contrast, Mcl-1 inhibition had no effect in FBW7 -WT CRCs., Conclusions: Our results demonstrate that Mcl-1 inhibitors can overcome intrinsic and acquired regorafenib resistance in CRCs by restoring apoptotic response. FBW7 mutations might be a potential biomarker predicting for response to the regorafenib/Mcl-1 inhibitor combination., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background and Aim: Slingshot 1 protein (SSH1) plays a critical role in cytoskeleton dynamic regulation. Increasing evidence suggest that SSH1 expression is upregulated in several cancers and relates to tumor progression and drug resistance. Here, we evaluated the role of SSH1 in colorectal cancer (CRC) development and its prognostic value in patients with CRC., Methods: SSH1 expression was examined by quantitative real-time polymerase chain reaction, western blot analysis, or immunohistochemistry. The association between SSH1 expression and clinical characteristics and prognosis was evaluated. Stable SSH1 knockdown cells were used for in vitro assays and xenograft models. Correlation between SSH1 expression and epithelial-mesenchymal transition (EMT) was analyzed by western blot and online data analysis., Results: SSH1 expression was upregulated in cancer tissue compared with paired non-cancerous tissue in patients with CRC. SSH1 expression level in CRC tissue was associated with tumor stage, lymph node metastasis, and correlated with poor prognosis as indicated by univariate and multivariate analyses. In vitro, loss of SSH1 impaired colony formation, migration, and invasion of CRC cells. In vivo data suggest that SSH1 could promote the progression and metastasis of CRC. Interestingly, E-cadherin, ZEB1, and Snail, which are markers of EMT, had a significant expression correlation with SSH1., Conclusions: SSH1 expression is associated with CRC progression and predicts poor prognosis. SSH1 may promote CRC tumor progression by regulating EMT., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: Anastomotic leakage (AL) is a catastrophic surgical complication affecting the prognosis of patients after colorectal surgery. We aimed to determine the value of the arterial calcification (AC) score in predicting AL., Methods: Medline and Embase were searched through November 2019. The odds ratio (OR) and 95% confidence interval (CI) were used to estimate the association between AC and AL after colorectal surgery. The fixed-effects model or random-effects model was adopted for data pooling. Subgroup analyses were conducted to assess the effect of different aortoiliac trajectories., Results: Four studies involving 496 patients were included. The calcium volume and calcium score measurements of different trajectories revealed a significant difference with regard to the left and right common iliac arteries, the superior mesenteric artery, and the left common iliac artery. Calcification of the internal iliac artery significantly increased the risk of AL compared with no AL (OR = 1.005; 95% CI 1.002-1.009; P = 0.005), as did calcification of the left internal iliac artery (OR = 1.009; 95% CI 1.002-1.016; P = 0.011), but not of the common iliac artery (OR = 1.001; 95% CI 1.000-1.001; P = 0.317) or common and internal iliac artery (OR = 1.000; 95% CI 1.000-1.000; P = 1.000)., Conclusions: AC is associated with increased risk of AL following colorectal surgery., Trial Registration: CRD42019141236.

Previous studies demonstrated that several inflammation-based hematological indices are closely related to various malignancies, including colorectal cancer (CRC). In this study, the prognostic value of inflammation-based markers, including a combination index termed coNLR-PDW, comprising the preoperative neutrophil-to-lymphocyte ratio (NLR) and the platelet distribution width (PDW), was evaluated in 206 patients with non-metastatic CRC treated with surgery at a single medical center. The association of patient demographics, blood chemistry, and serum biochemical indices with recurrence-free survival (RFS) and overall survival (OS) were examined through univariate and multivariate analysis. Receiver operating characteristic curve analysis revealed the optimal cut-off values of the NLR and lymphocyte-to-monocyte ratio (LMR) to be, respectively, 2.0 and 3.32 for both RFS and OS. For PDW, cut-off values of 17.25% and 17.35% were defined for RFS and OS, respectively. On univariate analysis, lymph node involvement, stage, presence of intravascular emboli (IVE), carbohydrate antigen 199 (CA199) ≥ 35 kU/L, NLR ≥ 2.0, LMR ≤ 3.32, elevated PDW, a high coNLR-PDW score, high blood glucose, and high neutrophil and lymphocyte percentages correlated with poorer RFS and OS (P < 0.05). On multivariate analysis, lymph node involvement, IVE, CA199, PDW, and coNLR-PDW correlated with both RFS and OS (P < 0.05), while NLR correlated only with OS (P = 0.001). These results highlight the usefulness of the coNLR-PDW index as a prognostic marker of non-metastatic CRC outcome. In clinical practice, its assessment could contribute to establishing more personalized regimes for patients undergoing tumor resection surgery.

Lymphovascular emboli is a prognostic factor in stage II CRC, but the significance of intravascular emboli (IVE) in stage III is unclear. Data from consecutive stage III CRC patients receiving radical surgery between January 2009 and November 2014 were retrospectively collected. The expression of CD133 was tested by immumohistochemical (IHC) staining. The potential prognosis risk factors were tested using univariate and multivariate survival analyses. IVE was significantly associated with CD133 expression (P < 0.001), gross tumor morphology (P = 0.001), histologic type (p < 0.001), lymph node status (pN) (p < 0.001), sub-class of stage III (p = 0.001), and serum CA199 level (p = 0.022). IVE, CD133 expression and lymph node status (pN) were independent risk factors for overall survival (OS) (p < 0.001, p = 0.003, and p = 0.008, respectively) and disease-free survival (DFS) (p < 0.001, p = 0.004, and p = 0.007, respectively) in stage III CRC. IVE might be an independent risk factor for the prognosis of stage III CRC patients after radical surgery. IVE might express a cancer stem cell (CSC) phenotype., Competing Interests: The authors declare that they have no competing interests.

Background: Neuron navigator 2 (NAV2) encodes a member of the neuron navigator gene family, which plays a role in tumorigenesis and cell migration. However, the prognostic value of NAV2 expression in colorectal cancer (CRC) patients and the potential pathway through which NAV2 promotes migration and invasion in CRC cell lines is poorly understood., Methods: The expression level of NAV2 was detected in CRC tissues from two different CRC cohorts by immunohistochemistry, qRT-PCR and Western blotting; the correlation between NAV2 expression and clinicopathological characters was analyzed, and the prognostic value of NAV2 expression was analyzed using a Cox regression model. CRC cell lines with NAV2 knocked out were used to validate the function and potential pathway used by NAV2 to promote CRC cell migration and invasion., Results: The results showed that NAV2 was overexpressed in CRC tissues, and it was closely correlated with depth of invasion, and lymph and distant metastasis. Multivariate analysis indicated that high NAV2 expression was a poor prognostic indicator of recurrence-free survival and overall survival in CRC patients. Furthermore, Cox regression analysis revealed that high NAV2 expression integrated with high tumor budding grade was a powerful independent predictive factor of CRC clinical outcome. In vitro and in vivo assays demonstrated that knockdown of NAV2 led to reduced migration and invasion of cancer cells, and the process involved the regulation of F-actin polymerization through the SSH1L/cofilin-1 pathway., Conclusion: Based on these findings, NAV2 could serve as both a prognostic biomarker and a potential therapeutic target for patients with NAV2-positive CRC.