Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB.

BACKGROUND: While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood. METHODS: We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses. RESULTS: Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy. CONCLUSIONS: Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.

Conditional survival and the prognostic value of serum carcinoembryonic antigen level in oldest old with colorectal cancer.

BACKGROUND: To evaluate the clinical value of serum CEA levels and their implications on the diagnostic value of the conventional TNM staging system in the oldest-old patients with colorectal cancer (CRC). METHODS: The recruited subjects were colorectal cancer patients aged 85 and older. The cutoff value for normal CEA level is 5 ng/mL. Patients with elevated CEA levels were categorized as stage C1, and those with normal CEA levels as stage C0. A number of Cox proportional hazard regression models were established to evaluate the prognosis of different prognostic factors with hazard ratios (HRs) and 95% confidence intervals (CIs). The Kaplan-Meier method was utilized to display the disparate prognostic impact of multiple clinicopathological factors with the log-rank test. RESULTS: A total of 17,359 oldest-old patients diagnosed with CRC were recruited from the SEER database. The conditional survival of oldest-old patients with CRC was dismal with a 1-year conditional survival of only 11%, 18%, and 30% for patients surviving 1, 3, and 5 years, respectively. Patients with stage C1 exhibited a 48.5% increased risk of CRC-specific mortality compared with stage C0 (HR = 1.485, 95%CI = 1.393-1.583, using stage C0 patients as the reference, P < 0.001). All the stage C0 patients indicated lower HRs relative to the corresponding stage C1 patients. CONCLUSIONS: Dismal conditional survival of oldest-old patients with CRC should be given additional consideration. C stage influences the prognosis of oldest-old patients with CRC.

Use of lymph node ratio to guide clinical decision-making concerning adjuvant radiotherapy in pT1-2N1 rectal cancer.

PURPOSE: Lymph node metastases are uncommon in pT1-2 rectal cancer. pT1-2N1 are often characterized with low tumor burden and intermediate prognosis. Therefore, adjuvant radiotherapy (ART) is controversial in these patients. This study aimed to investigate the value of ART in pT1-2 rectal cancer and evaluate the guiding role of lymph node ratio (LNR) for utilization of ART. METHODS: pT1-2N1 rectal cancer patients who received surgery without neoadjuvant radiotherapy between 2000 and 2018 with at least 12 lymph node harvest were extracted from the Surveillance, Epidemiology and End Results (SEER) database. We used time-dependent receiver operating characteristic (ROC) analysis to determine the optimal cutoff of LNR. Kaplan-Meier methods and Cox proportional hazards regression models were performed to determine the prognostic value of ART in pT1-2N1 rectal cancer patients and subgroups stratified by LNR. RESULTS: A total of 674 and 1321 patients with pT1N1 and pT2N1 rectal cancer were eligible for analysis. There was no statistical cancer-specific survival (CSS) difference in pT1N1 rectal cancer patients between receiving and not receiving ART (P = 0.464). The 5-year CSS was 89.6% and 83.2% in pT2N1 rectal cancer patients between receiving and not receiving ART, respectively (P = 0.003). A total of 7.0% was identified as the optimal cutoff value of LNR. Survival improvement offered by ART was only found in LNR ≥ 7.0% subgroup (5-year CSS: 89.5% versus 79.6%, P = 0.003) instead of LNR < 7.0% subgroup (5-year CSS: 89.9% versus 86.3%, P = 0.208). CONCLUSION: ART show substantial survival benefit in pT2N1 rectal cancer patients with LNR ≥ 7.0%, warranting the conventional adoption of ART in this subgroup.

A novel epithelial-mesenchymal transition molecular signature predicts the oncological outcomes in colorectal cancer.

Epithelial-mesenchymal transition (EMT), a biological process involving the transformation of epithelial cells into mesenchymal cells, promotes tumour initiation and metastasis. The aim of this study was to construct an EMT molecular signature for predicting colorectal cancer (CRC) prognosis and evaluate the efficacy of the model. The risk scoring system, constructed by log-rank test and multivariate Cox regression analysis according to EMT-related gene expression in CRC patients from TCGA database, demonstrated the highest correlation with prognosis compared with other parameters in CRC patients. The risk scores were significantly correlated with more lymph node metastasis, distal metastasis and advanced clinical stage of CRC. The model was further successfully validated in two independent external cohorts from GEO database. Furthermore, we developed a nomogram to integrate the EMT signature with the pathological stage of CRC, which was found to perform well in predicting the overall survival. Additionally, this risk scoring model was found to be associated with immune cell infiltration, implying a potential role of EMT involved in immunity regulation in tumour microenvironment. Taken together, our novel EMT molecular model may be useful in identifying high-risk patients who need an intensive follow-up and more aggressive therapy, finally contributing to more precise individualized therapeutic strategies.

Development and validation of a novel epigenetic signature for predicting prognosis in colon cancer.

Epigenetic factors play a critical role in carcinogenesis by imparting a distinct feature to the chromatin architecture. The present study aimed to develop a novel epigenetic signature for evaluating the relapse-free survival of colon cancer patients. Public microarray datasets were acquired from the Gene Expression Omnibus databases: GSE39582, GSE17538, GSE33113, and GSE37892 set. Patients from GSE39582 set were randomized 1:1 into training and internal validation series. Patients were divided into high-risk and low-risk groups in training series based on a set of 11 epigenetic factors (p < .001). The good reproducibility for the prognostic value of the epigenetic signature was confirmed in the internal validation series (p < .001), external validation series (a combination of GSE17538 set, GSE33113 set, and GSE37892 set; p = .018), and entire series (p < .001). Furthermore, a nomogram, which integrated the epigenetic signature, pathological stage, and postoperative chemotherapy, was developed based on the GSE39582 set. The time-dependent receiver operating characteristic curve at 1 year demonstrated that the comprehensive signature presented superior prognostic value than the pathological stage. In conclusion, an epigenetic signature, which could be utilized to divide colon cancer patients into two groups with significantly different risk of relapse, was established. This biomarker would aid in identifying patients who require an intensive follow-up and aggressive therapeutic intervention.

ACRNaCT trial protocol: efficacy of adjuvant chemotherapy in patients with clinical T3b/T4, N+ rectal Cancer undergoing Neoadjuvant Chemoradiotherapy: a pathology-oriented, prospective, multicenter, randomized, open-label, parallel group clinical trial.

BACKGROUND: The CAO/ARO/AIO-94 demonstrated that neoadjuvant chemoradiotherapy (CRT) could decrease the rate of local recurrence rather than distal metastases in advanced rectal cancer. Adjuvant chemotherapy (ACT) can eliminate micrometastasis, and render a better prognosis to rectal cancer. However, adoption of ACT mainly depends on the evidence from colon cancer. Neoadjuvant CRT can lead to tumor shrinkage in a number of patients with advanced rectal cancer. The administration of adjuvant therapy depending on pretreatment clinical stage or postoperative yield pathological (yp) stage remains controversial. At present, the clinical guidelines recommend ACT for patients with stage II/III (ypT3-4 N0 or ypTanyN1-2) rectal cancer following neoadjuvant CRT and surgery. However, the yp stage may influence the guidance of ACT. METHODS: According to the postoperative pathological stage, the present study was divided into two parts with different study design procedures. Patients will undergo different therapeutic strategies after collecting data related to postoperative pathological stage. For patients with pathologic complete response or yp stage I, the study was designed as a non-inferiority trial to compare the patients' long-term outcomes in observational group and those in treatment group with 5-fluorouracil. For patients at yp stage II or III, the study was designed as a superiority trial to compare the oncological effect of oxaliplatin combined with 5-fluorouracil, in addition to 5-fluorouracil alone in ACT. The primary endpoint is 3-year disease-free survival (DFS). Secondary endpoints are 3-year, 5-year overall survival, 5-year DFS, and the rate of local recurrence and adverse events resulted from chemotherapy and the patients' quality of life postoperatively. DISCUSSION: The ACRNaCT trial aims to investigate whether observation is not inferior than 5-fluorouracil for pathologic complete response or yp stage I, and indicate whether combined chemotherapy contains superior outcomes than 5-fluorouracil alone for yp stage II or III in patients receiving neoadjuvant CRT and surgery for locally advanced rectal cancer (LARC). This trial is expected to provide individualized adjuvant treatment strategies for LARC patients following neoadjuvant CRT and surgery. TRIAL REGISTRATION: The trial has been registered in ClinicalTrials.gov on January 30, 2018 (Registration No. NCT03415763), and also, that was registered in Chinese Clinical Trial Registry on November 12, 2018 (Registration No. ChiCTR1800019445).

MiR-592 Promotes Gastric Cancer Proliferation, Migration, and Invasion Through the PI3K/AKT and MAPK/ERK Signaling Pathways by Targeting Spry2.

BACKGROUND/AIMS: Gastric cancer (GC) is one of the most prevalent digestive malignancies. MicroRNAs (miRNAs) are involved in multiple cellular processes, including oncogenesis, and miR-592 itself participates in many malignancies; however, its role in GC remains unknown. In this study, we investigated the expression and molecular mechanisms of miR-592 in GC. METHODS: Quantitative real-time PCR and immunohistochemistry were performed to determine the expression of miR-592 and its putative targets in human tissues and cell lines. Proliferation, migration, and invasion were evaluated by Cell Counting Kit-8, population doubling time, colony formation, Transwell, and wound-healing assays in transfected GC cells in vitro. A dual-luciferase reporter assay was used to determine whether miR-592 could directly bind its target. A tumorigenesis assay was used to study whether miR-592 affected GC growth in vivo. Proteins involved in signaling pathways and the epithelial-mesenchymal transition (EMT) were detected with western blot. RESULTS: The ectopic expression of miR-592 promoted GC proliferation, migration, and invasion in vitro and facilitated tumorigenesis in vivo. Spry2 was a direct target of miR-592 and Spry2 overexpression partially counteracted the effects of miR-592. miR-592 induced the EMT and promoted its progression in GC via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2. CONCLUSIONS: Overexpression of miR-592 promotes GC proliferation, migration, and invasion and induces the EMT via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2, suggesting a potential therapeutic target for GC.

Klotho negatively regulated aerobic glycolysis in colorectal cancer via ERK/HIF1α axis.

BACKGROUND: Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers, including colorectal cancer. Recent years have witnessed the importance of metabolism transformation in cancer cell malignancies maintenance. Aberrant cancer cell metabolism is considered to be the hallmark of cancer. Our previous studies demonstrated that KL played negative roles in colon cancer cell proliferation and metastasis. However, its role in the cancer cell reprogramming has seldom been reported. The aim of this study was to examine the role of KL in aerobic glycolysis in colorectal cancer. METHODS: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and KL expression in colorectal cancer tissues. The impact of KL on glucose metabolism and its mechanisms were further validated in vitro and in vivo. RESULTS: Patients with lower KL expression exhibited higher 18F-FDG uptake (P < 0.05), indicating that KL might participate in aerobic glycolysis regulation. In vitro assay by using colon cancer cell lines further supported this observation. By overexpressing KL in HTC116 and SW480 cells, we observed that the glycolysis was inhibited and the mitochondrial respiration increased, indicating that KL was a negative regulator of aerobic glycolysis. To seek for the underlying mechanisms, we tried to dig out the relation between KL and HIF1α signaling pathway, and found that KL negatively regulated HIF1α protein level and transcriptional activity. Western blot analysis showed that KL overexpression negatively regulated ERK pathway, and KL regulated aerobic glycolysis in part through its regulation of ERK/ HIF1α axis. CONCLUSIONS: Taken together, KL is a negative regulator of aerobic glycolysis and KL inhibited glucose metabolism transformation via the ERK/ HIF1α axis.

Real-world study of a novel prognostic scoring system: for a more precise prognostication and better clinical treatment guidance in stages II and III colon cancer.

PURPOSE: This study aimed to improve the American Joint Committee on Cancer (AJCC) Tumor Node Metastases (TNM) staging system and demonstrate the improvement in prognostic accuracy and clinical management guidance in colon cancer using the novel prognostic score (P score). METHODS: Eligible patients were identified using the Surveillance, Epidemiology, and End Results database. A P score (based on age, tumor size, and tumor grade) was assigned to each patient. The Cox proportional hazards regression analyses were performed to identify independent factors associated with prognosis. The Kaplan-Meier survival curves were used to analyze the prognosis of patients with colon cancer with different P scores. The TNM staging system was compared with the P score in stages I-IV by calculating the concordance index. RESULTS: The multivariate Cox analysis indicated that a higher P score was independently associated with a higher risk of cancer-specific mortality. The Kaplan-Meier survival curves showed that the survival benefit gradually increased as the P score decreased. The concordance index rose from 0.5, 0.593, 0.633, and 0.551 of AJCC TNM staging system to 0.709, 0.651, 0.691, and 0.623 of P score in stages I-IV, respectively. CONCLUSIONS: The P score was an independent prognostic factor of colon cancer and had a much better prognostic accuracy than the AJCC TNM staging system in all patients with colon cancer. It may help in identifying patients with high-risk stage II colon cancer who were candidates for adjuvant therapy and differentiating patients with stage III colon cancer for adjuvant therapy.

Prognostic value of distant metastasis sites and surgery in stage IV colorectal cancer: a population-based study.

PURPOSE: We investigated the prognostic value of distant metastasis sites among patients with metastatic colorectal cancer (CRC) and the significance of metastasectomy and resection of the primary CRC. METHODS: Between 2010 and 2014, patients diagnosed with metastatic colorectal adenocarcinoma were selected using the surveillance, epidemiology, and end results (SEER) database. The prognosis of these patients was compared according to the site of metastasis (liver, lung, bone, and brain). A total of 15,133 patients suffered from isolated organ involvement, while 5135 patients experienced multiple organ metastases. RESULTS: In the isolated organ metastasis cohort, median overall survival (OS) for patients with liver, lung, bone, and brain metastases was 16, 20, 7, and 5 months, respectively. Patients with isolated lung metastases had better cancer-specific survival (CSS) and OS as compared to patients with metastases at any other sites (p < 0.0001 for both CSS and OS). Patients with isolated liver metastases had better prognosis as compared to patients with isolated bone or brain metastases (p < 0.0001 for both CSS and OS). Moreover, patients with a single metastatic site had better prognosis than patients with multiple organs involved (p < 0.0001 for both CSS and OS). Multivariate analysis in patients with isolated organ metastases demonstrated that age ≤ 60 years, rectal cancer, being married, non-black race, N0 stage, and surgery of the primary and distant lesions showed more favorable prognosis. CONCLUSIONS: The metastatic site was an independent prognostic factor in stage IV colorectal cancer. Also, carefully chosen patients may benefit from surgery.

Correction: Zhang et al. Clinical Management of Low Anterior Resection Syndrome: Review of the Current Diagnosis and Treatment. Cancers 2023, 15, 5011.

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Pretreatment Carcinoembryonic Antigen Level Serves as a Potential Biomarker to Guide Adjuvant Radiotherapy in pT4N+ Colon Cancer Patients.

The survival benefit of adjuvant radiotherapy in T4 colon cancer (CC) remains controversial, with conflicting results reported in the literature. This study aimed to explore the relationship between pretreatment carcinoembryonic antigen (CEA) level and overall survival (OS) of pT4N+ CC patients treated with adjuvant radiotherapy. Data of pT4N+ CC patients who received curative surgery between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The primary outcome was OS, and subgroup analysis was conducted according to pretreatment CEA level. A total of 8763 patients were eligible for our study. In the CEA-normal group, 151 patients received adjuvant radiotherapy, while 3932 patients did not. In the CEA-elevated group, 212 patients received adjuvant radiotherapy, while 4468 patients did not. In general, adjuvant radiotherapy was associated with better OS in pT4N+ CC patients (HR = 0.846, 95% CI = 0.733-0.976, P = 0.022). Intriguingly, only patients with an elevated pretreatment CEA level gained a survival benefit from adjuvant radiotherapy (HR = 0.782; 95% CI = 0.651-0.939; P = 0.008) while those with a normal pretreatment CEA level did not (HR = 0.907; 95% CI = 0.721-1.141; P = 0.403). Multivariable Cox regression analysis demonstrated that adjuvant radiotherapy was an independent protective factor in pT4N+ CC patients with an elevated pretreatment CEA level. Pretreatment CEA levels could serve as a potential biomarker to screen pT4N+ CC patients who would benefit from adjuvant radiotherapy.

Effect of interval between neoadjuvant chemoradiotherapy and surgery on oncological outcomes in poor responders with locally advanced rectal cancer: a retrospective cohort study.

BACKGROUND: The optimal interval from completion of neoadjuvant chemoradiotherapy (CRT) to surgery in locally advanced rectal cancer remains controversial. It seems that delayed surgery is associated with an increase in pathological complete response rates. However, the prognostic effect of delayed surgery in poor responders is unclear. MATERIALS AND METHODS: Patients with locally advanced mid or distal rectal cancer undergoing neoadjuvant CRT followed by total mesorectal excision at a university teaching cancer center between June 2010 and December 2018 were retrospectively reviewed in this study. According to the tumor regression grade, poor responders (tumor regression grade 2-3) to neoadjuvant CRT were selected for analyses. Patients were divided into the longer interval group (greater than 8 weeks) and the shorter interval group (8 weeks or less) based on the wait time from completion of neoadjuvant CRT therapy to surgery. Results: among 916 eligible patients, 522 patients had a poor tumor response. There were 217 patients in the shorter interval group and 305 patients in the longer interval group. At the baseline, patients in the longer interval group were more likely to have a T3 stage and positive vascular invasion. Compared with patients in the shorter interval group, patients in the longer interval group had significantly worse overall survival and disease-free survival (DFS) (log-rank test, overall survival: P =0.004, DFS: P <0.001). The 3-year DFS rates were 75.6 and 63.1% in the shorter interval group and the longer interval group, respectively. In the multivariate analysis, delayed surgery was associated with an increased risk of mortality (hazard ratio: 2.003, 95% CI: 1.233-3.253, P =0.005) and recurrence (hazard ratio: 1.555, 95% CI: 1.121-2.156, P =0.008). CONCLUSION: Patients who had a poor tumor response should be identified by restaging MRI and receive radical surgery in time, without a prolonged interval.

circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer.

BACKGROUND: Circular RNAs (circRNAs) generated by back-splicing of precursor mRNAs (pre-mRNAs) are often aberrantly expressed in cancer cells. Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers, including colorectal cancer (CRC). However, the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited. Here, we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis. METHODS: circRNA microarray was performed with three pairs of tumor and non-tumor tissues from CRC patients. The expression of circRNAs were determined by quantitative PCR (qPCR) and in situ hybridization (ISH). The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs. The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array, RNA pull-down/mass spectrometry, RNA immunoprecipitation assay, luciferase reporter assay, chromatin immunoprecipitation analysis, and fluorescence in situ hybridization (FISH). RESULTS: Among circRNAs, circCAPRIN1 was most significantly upregulated in CRC tissue specimens. circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients. Downregulation of circCAPRIN1 suppressed proliferation, migration, and epithelial-mesenchymal transition of CRC cells, while circCAPRIN1 overexpression had opposite effects. RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism. Moreover, circCAPRIN1 promoted lipid synthesis by enhancing Acetyl-CoA carboxylase 1 (ACC1) expression. Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2 (STAT2) to activate ACC1 transcription, thus regulating lipid metabolism and facilitating CRC tumorigenesis. CONCLUSIONS: These findings revealed the oncogenic role and mechanism of circCAPRIN1 in CRC. circCAPRIN1 interacted with STAT2 to promote CRC tumor progression and lipid synthesis by enhancing the expression of ACC1. circCAPRIN1 may be considered as a novel potential diagnostic and therapeutic target for CRC patients.

Clinical Management of Low Anterior Resection Syndrome: Review of the Current Diagnosis and Treatment.

BACKGROUND: Low anterior resection syndrome (LARS) is a series of bowel dysfunction symptoms, including altered bowel frequency, irregular bowel rhythms, fecal incontinence, and constipation. LARS occurs in 80% of patients undergoing sphincter-preserving surgery, affecting patients' quality of life along with social avoidance. Different measurements and treatments have been raised to deal with LARS, but no systematic standard has been developed. OBJECTIVE AND METHODS: To promote the standardization of clinical trials and clinical management of LARS, this review summarizes the latest findings up until 2023 regarding the diagnostic criteria, assessment protocols, and treatment modalities for postoperative LARS in rectal cancer. RESULTS: The diagnostic criteria for LARS need to be updated to the definition proposed by the LARS International Collaborative Group, replacing the current application of the LARS score. In both clinical trials and clinical treatment, the severity of LARS should be assessed using at least one symptom assessment questionnaire, the LARS score or MSKCC BFI, and at least one scale related to quality of life. Anorectal manometry, fecoflowmetry, endoscopic ultrasonography, and pelvic floor muscle strength testing are recommended to be adopted only in clinical trials. After analysis of the latest literature on LARS treatment, a stepwise classification model is established for the standardized clinical management of LARS. Patients with minor LARS can start with first-line treatment, including management of self-behavior with an emphasis on diet modification and medication. Lamosetron, colesevelam hydrochloride, and loperamide are common antidiarrheal agents. Second-line management indicates multi-mode pelvic floor rehabilitation and transanal irrigation. Patients with major LARS should select single or several treatments in second-line management. Refractory LARS can choose antegrade enema, neuromodulation, or colostomy. CONCLUSIONS: In clinical trials of LARS treatment between 2020 and 2022, the eligibility criteria and evaluation system have been variable. Therefore, it is urgent to create a standard for the diagnosis, assessment, and treatment of LARS. Failure to set placebos and differentiate subgroups are limitations of many current LARS studies. Randomized controlled trials comparing diverse therapies and long-term outcomes are absent, as well. Moreover, a new scale needs to be developed to incorporate the patient's perspective and facilitate outpatient follow-up. Though the establishment of a stepwise classification model for LARS treatment here is indispensable, the refinement of the guidelines may be improved by more standardized studies.

CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression.

BACKGROUND: UTX (encoded by KDM6A), a histone demethylase for H3K27me2/3, is frequently mutated in human cancers. However, its functional and regulatory mechanisms in colorectal cancer (CRC) remain unclear. METHODS: Immunohistochemistry staining was used to investigate the clinical relevance of UTX in CRC. Additionally, we generated a spontaneous mouse CRC model with conditional Utx knockout to explore the role of UTX in the colorectal tumorigenesis. Post-translational regulation of UTX was determined by co-immunoprecipitation and immunoblot analyses. RESULTS: Herein, we identify that downregulation of UTX, mediated by the Cullin 4B-DNA Damage Binding Protein-1-Constitutive Photomorphogenesis Protein 1 (CUL4B-DDB1-COP1) complex, promotes CRC progression. Utx deletion in intestinal epithelial cells enhanced the susceptibility to tumorigenesis in AOM/DSS-induced spontaneous mouse CRC model. However, this effect is primarily alleviated by GSK126, an inhibitor of histone methyltransferase EZH2. Mechanistically, EMP1 and AUTS2 are identified as putative UTX target genes mediating UTX functions in limiting intestinal tumorigenesis. Notably, the CUL4B-DDB1-COP1 complex is identified as the functional E3 ligase responsible for targeting UTX for degradation in CRC cells. Thus, Cop1 deficiency in mouse intestinal tissue results in UTX accumulation and restricts tumorigenesis. Furthermore, patient cohort analysis reveals that UTX expression is negatively correlated with clinical stage, favorable disease outcomes, and COP1 expression. CONCLUSIONS: In the current study, the tumor suppressor function and regulation of UTX in CRC provide a molecular basis and the rationale to target EZH2 in UTX-deficient CRC.

Identification of XAF1 as an endogenous AKT inhibitor.

AKT kinase is a key regulator in cell metabolism and survival, and its activation is strictly modulated. Herein, we identify XAF1 (XIAP-associated factor) as a direct interacting protein of AKT1, which strongly binds the N-terminal region of AKT1 to block its K63-linked poly-ubiquitination and subsequent activation. Consistently, Xaf1 knockout causes AKT activation in mouse muscle and fat tissues and reduces body weight gain and insulin resistance induced by high-fat diet. Pathologically, XAF1 expression is low and anti-correlated with the phosphorylated p-T308-AKT signal in prostate cancer samples, and Xaf1 knockout stimulates the p-T308-AKT signal to accelerate spontaneous prostate tumorigenesis in mice with Pten heterozygous loss. And ectopic expression of wild-type XAF1, but not the cancer-derived P277L mutant, inhibits orthotopic tumorigenesis. We further identify Forkhead box O 1 (FOXO1) as a transcriptional regulator of XAF1, thus forming a negative feedback loop between AKT1 and XAF1. These results reveal an important intrinsic regulatory mechanism of AKT signaling.

Incidence, predictors and prognostic implications of positive circumferential resection margin in colon cancer: A retrospective study in a Chinese high-volume cancer center.

Positive circumferential resection margin (CRM) was associated with a higher recurrence rate and worse survival in rectal cancer. Predictors of CRM in rectal cancer have widely been investigated. Our study aims to determine the incidence, predictors and prognostic implications of positive CRM following colon cancer (CC) surgery in a Chinese high-volume cancer center. The clinicopathological features and oncological outcomes of CC patients undergoing surgery between January 2008 and December 2018 were identified from Fudan University Shanghai Cancer Center database. Positive CRM was defined as resection margin ≤1 mm. A total of 5268 stage I-IV CC patients were identified in our study, 108 (2.05%) of whom had positive CRM. Multivariate logistic analysis found that advanced N stage, distant metastases and poorly differentiated tumor had increased risk of positive CRM. After propensity score matching, the 5-year overall survival rates of the patients with positive and negative CRM were 33.2% and 39.8% (P=0.005), respectively. Multivariable COX regression model showed that positive CRM was an independent prognostic factor for OS in CC patients. The overall rate of positive CRM in our center is lower than that in western population. Several adverse pathological parameters deserve more attention to identify CC patients at a high risk of positive CRM. Adoption of appropriate surgical techniques and multidisciplinary treatment planning are expected to improve oncological outcomes for high selected CC patients with "high-risk" CRM involvement.

Tumor Regression Grade as a Prognostic Factor in Metastatic Colon Cancer Following Preoperative Chemotherapy.

BACKGROUND: The prognostic value of tumor regression grade (TRG) in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy has been explored extensively. However, whether TRG is predictive of outcome in colon cancer following preoperative chemotherapy has not been reported. MATERIALS AND METHODS: A total of 276 colon cancer patients who had undergone preoperative chemotherapy and surgery in Fudan University Shanghai Cancer Center during the period March 2014 through November 2019 were recruited in this study. 113 (40.9%) and 163 (59.1%) patients were diagnosed with locally advanced colon cancer (LACC) and metastatic colon cancer (mCC) before preoperative chemotherapy, respectively. The TRG was divided into TRG0 (complete response), TRG1 (good response), TRG2 (moderate response), and TRG3 (poor response). RESULTS: Of the 276 patients 4.0% were TRG0, 5.4% were TRG1, 29.3% were TRG2, 61.2% were TRG3. TRG0 and TRG1 or TRG0, TRG1 and TRG2 were combined to simplify analysis due to limited sample size. In entire cohort, the 3-year overall survival for TRG0-1, TRG2, and TRG3 groups were 80.0%, 68.8% and 43.3% (P = .003). In LACC cohort, TRG was not associated with patients' prognosis, which largely resulted from limited outcome events. In mCC cohort, the 3-year overall survival for TRG0-1, TRG2, and TRG3 groups were 74.3%, 62.8% to 28.1% (P<0.001). Multivariate analysis demonstrated that TRG was an independent prognostic factor for overall survival in both entire cohort and mCC cohort (TRG3 vs. TRG0-2). CONCLUSION: TRG is a prognostic factor in predicting long-term outcomes of mCC patients treated with preoperative chemotherapy.