Loss of Hippo tumor-suppressor activity and hyperactivation of YAP are commonly observed in cancers. Inactivating mutations of Hippo kinases MST1/2 are uncommon, and it remains unclear how their activity is turned off during tumorigenesis. We identified STRN3 as an essential regulatory subunit of protein phosphatase 2A (PP2A) that recruits MST1/2 and promotes its dephosphorylation, which results in YAP activation. We also identified STRN3 upregulation in gastric cancer correlated with YAP activation and poor prognosis. Based on this mechanistic understanding and aided by structure-guided medicinal chemistry, we developed a highly selective peptide inhibitor, STRN3-derived Hippo-activating peptide, or SHAP, which disrupts the STRN3-PP2Aa interaction and reactivates the Hippo tumor suppressor, inhibits YAP activation, and has antitumor effects in vivo. ll

Background Patients with colorectal adenoma polyps (PLP) are at higher risk of developing colorectal cancer (CRC). However, the development of improved and robust biomarkers to enable screening, surveillance and early detection of PLP and CRC continues to be a challenge. The aim of this study was to identify biomarkers of progression to CRC by metabolomic profiling of human serum samples using a multistage approach. Methods Metabolomic profiling was conducted using Metabolon platform for 30 PLP, 30 CRC and 30 control subjects followed by targeted validation of top metabolites in an additional set of 50 CRC, 50 PLP and 50 controls using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Unconditional multivariable logistic regression models adjusted for covariates were used to evaluate association with PLP and CRC risks. Results For the discovery phase, 404 serum metabolites were detected with 50 metabolites showing differential levels between PLP, CRC and controls (P for trend<0.05). Following validation, three top metabolites (xanthine, hypoxanthine and D-mannose) were validated showing lower levels of xanthine and hypoxanthine and higher level of D-mannose in PLP and CRC cases compared to controls. Further exploratory analysis of metabolic pathways revealed key roles for urea cycle and caffeine metabolism associated with PLP and CRC risks. Additionally, joint effect of top metabolites with smoking and significant interaction with BMI were also observed. Analysis of hypoxanthine to xanthine levels as ratio indicated association with CRC progression. Conclusions Our results suggest the potential utility of circulating metabolites as novel biomarkers for early detection of CRC.

Circulating tumor cells (CTCs) are cancer cells shed from either the primary tumor or its metastases that circulate in the peripheral blood. The CTCs are regarded as the source of tumor recurrence and metastasis and speculated as the indicators of residual tumors, thereby indicating a poor prognosis. Although CTCs play a vital role in tumor metastasis and recurrence, little is known about the underlying survival mechanisms in the blood circulation. The accumulating evidence has revealed that CTCs might survive in the peripheral blood by overcoming the mechanical damage due to shear stress, resistance to anoikis, evasion of immune destruction, and resistance to chemotherapy. The present review addresses the putative survival mechanisms underlying the formation and migration of CTCs according to their biological characteristics and blood microenvironment. In addition, the relationship between CTCs and microenvironment is illustrated, and the influencing factors related to the interactions of CTCs with various components in the peripheral blood are reviewed with respect to the platelets, immune cells, cytokines, and circulating tumor microemboli (CTM). Furthermore, the recent advances in the new treatment strategies targeting the survival mechanisms of CTCs are also discussed.

More than 50% of patients with colorectal cancer (CRC) are initially diagnosed with locally advanced CRC (LACRC), and half of those patients develop recurrence or metastasis after resection. Here, we investigated whether the novel index HALP, which is a combination of preoperative hemoglobin, albumin, lymphocyte and platelet levels, correlates with survival in LACRC patients. A total of 820 patients with LACRC from two independent hospitals were included in our study. The correlations between HALP and overall and cancer-specific survival were calculated using training and validation sets. Lower HALP values correlated with an increased risk of death and cancer-related death in both sets. Moreover, the risk score based on HALP allowed stratification of patients into distinct prognostic groups with greater accuracy than previously proposed indexes. These results suggest that HALP may be useful as a clinical prognostic factor for patients with LACRC.

Purpose To evaluate the effects of single-nucleotide polymorphisms (SNPs) in microRNA-related genes on clinical outcomes in colorectal cancer (CRC) patients receiving first-line fluoropyrimidine-based chemotherapy. Experimental Design Forty-one SNPs in 26 microRNA-related genes were genotyped in 1,097 CRC patients recruited at the University of Texas MD Anderson Cancer Center. Patients were enrolled between 1990 and 2008 and last follow-up was in 2010. The associations between genotypes and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) stratified by clinical stage were analyzed in 741 newly diagnosed patients (diagnosed within 1 year) and replicated the findings in additional 356 patients. Results In patients with stage III disease, mir608:rs4919510 was associated with increased risk for both recurrence (HR=2.72; 95%CI, 1.38 to 5.33) and death (HR=3.53; 95%CI, 1.42 to 8.73). The associations were confirmed in the replication set and the combined HR for training and replication sets was 1.94 (95% CI, 1.31 to 2.86) for recurrence and 2.35 (95%CI, 1.40 to 3.93) for death, respectively. The mir219-1:rs213210 showed consistent association with death in the training set (HR=3.86; 95%CI, 1.33 to11.22), the replication set (HR = 3.33; 95% CI, 1.39 to 7.98) and combined dataset (HR = 3.53; 95% CI, 1.80 to 6.95). In combined analysis of these two SNPs, patients carrying the variant genotypes at both sites exhibited a 5.6 fold increased risk of death. Conclusion Genetic polymorphisms in the microRNA pathway may predict prognosis in stage III CRC patients treated with fluoropyrimidine-based chemotherapy.

Background Colorectal cancer (CRC) is one of the most malignant tumors with high incidence, yet its molecular mechanism is not fully understood, hindering the development of targeted therapy. Metabolic abnormalities are a hallmark of cancer. Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy. In this study, we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms. Methods We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC. Squalene epoxidase (SQLE) was identified to be highly upregulated in CRC patients. The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability, colony and organoid formation, intracellular cholesterol concentration and xenograft tumor growth. The molecular mechanism of SQLE function was explored by combining transcriptome and untargeted metabolomics analysis. Western blotting and real‐time PCR were used to assess MAPK signaling activation by SQLE. Results SQLE‐related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis. SQLE promoted CRC growth in vitro and in vivo. Inhibition of SQLE reduced the levels of calcitriol (active form of vitamin D3) and CYP24A1, followed by an increase in intracellular Ca2+ concentration. Subsequently, MAPK signaling was suppressed, resulting in the inhibition of CRC cell growth. Consistently, terbinafine, an SQLE inhibitor, suppressed CRC cell proliferation and organoid and xenograft tumor growth. Conclusions Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1‐mediated MAPK signaling, highlighting SQLE as a potential therapeutic target for CRC treatment.

Neutrophils are found to be infiltrated in tumour tissues of patients with colitis-associated cancer (CAC) and colorectal cancer (CRC), and CD177 is mainly expressed in neutrophils. In our study, expression of CD177 in tumour tissues from patients with CAC or CRC was analysed byquantitative real-time polymerase chain reaction, flow cytometry and immunohistochemistry. We recruited 378 patients with CRC, determined CD177 expression in tumours and examined its correlation with clinicopathological features. Moreover, CAC model was induced in wild-type and CD177-/- mice by azoxymethane/dextran sodium sulphate. CD177+ neutrophils were significantly increased in colon tumour tissues from patients with CRC or CAC compared with controls. Expression of CD177 mRNA and percentages of CD177+ neutrophils were also markedly increased in tumour tissues from CRC patients compared with controls. Patients with high density of CD177+ neutrophils had better overall survival and disease-free survival compared with controls. Multivariate analyses revealed that the density of CD177+ neutrophils was an independent factor in predicting overall survival and disease-free survival. Consistently, CD177 depletion aggravated azoxymethane/dextran sodium sulphate-induced CAC in mice. Expression of Ki67 and proliferating cell nuclear antigen was increased in tumour tissues from CD177-/- mice compared with wild-type counterparts. Moreover, CD177-/- neutrophils failed to migrate in response to fMLP[AU: Please expand fMLP, DN, TNM and HIF-1α.] stimulation compared with wild-type controls. Our data indicate that CD177+ neutrophils suppress epithelial cell tumourigenesis and act as an independent factor in predicting the prognosis in patients with CRC. CD177+ neutrophils may serve as a novel therapeutic target in the treatment and predict the prognosis of CAC and CRC.

BACKGROUND Lymphovascular invasion (LVI) is suggested to be an early and important step in tumor progression toward metastasis, but its prognostic value and genetic mechanisms in colorectal cancer (CRC) have not been well investigated. AIM To investigate the prognostic value of LVI in CRC and identify the associated genomic alterations. METHODS We performed a retrospective analysis of 1219 CRC patients and evaluated the prognostic value of LVI for overall survival by the Kaplan-Meier method and multivariate Cox regression analysis. We also performed an array-based comparative genomic hybridization analysis of 47 fresh CRC samples to examine the genomic alterations associated with LVI. A decision tree model was applied to identify special DNA copy number alterations (DCNAs) for differentiating between CRCs with and without LVI. Functional enrichment and protein-protein interaction network analyses were conducted to explore the potential molecular mechanisms of LVI. RESULTS LVI was detected in 150 (12.3%) of 1219 CRCs, and the presence was positively associated with higher histological grade and advanced tumor stage (both P < 0.001). Compared with the non-LVI group, the LVI group showed a 1.77-fold (95% confidence interval: 1.40-2.25, P < 0.001) increased risk of death and a significantly lower 5-year overall survival rate ( P < 0.001). Based on the comparative genomic hybridization data, 184 DCNAs (105 gains and 79 losses) were identified to be significantly related to LVI ( P < 0.05), and the majority were located at 22q, 17q, 10q, and 6q. We further constructed a decision tree classifier including seven special DCNAs, which could distinguish CRCs with LVI from those without it at an accuracy of 95.7%. Functional enrichment and protein-protein interaction network analyses revealed that the genomic alterations related to LVI were correlated with inflammation, epithelial-mesenchymal transition, angiogenesis, and matrix remodeling. CONCLUSION LVI is an independent predictor for survival in CRC, and its development may correlate with inflammation, epithelial-mesenchymal transition, angiogenesis, and matrix remodeling.