BRAF-mutant microsatellite-stable rectal cancer with acquired KRAS mutation leading to drug resistance in liver metastasis.

BRAF-mutant microsatellite-stable colorectal cancer (CRC), metastasized to distant sites, is associated with a poor prognosis. However, the BEACON CRC regimen, comprising a BRAF inhibitor, MEK inhibitor, and anti-EGFR antibody, offered a prolonged prognosis. Nonetheless, resistance to this regimen may occur, as observed in our reported case of CRC, where a KRAS mutation was identified in addition to the BRAF V600E mutation. Here, we present a case of 74-year-old woman with rectal cancer (pT4bN1bM0 Stage IIIc) harboring the BRAF V600E mutation. After resection of the primary tumor and during adjuvant chemotherapy using CAPOX (capecitabine and oxaliplatin), liver and lung metastases became apparent, and a companion diagnosis test revealed the presence of a BRAF V600E mutation. The new lesions were deemed resistant to the CAPOX regimen, and we decided to introduce encorafenib and cetuximab. After resection of liver metastases, encorafenib and cetuximab were reintroduced, but a new lesion appeared in hepatic S7, indicating resistance to the encorafenib and cetuximab regimen. The resistant liver metastasis was subsequently resected. To elucidate the resistance mechanism, we conducted a comprehensive analysis using the FoundationOne CDx cancer gene panel test, revealing the presence of a KRAS Q61H mutation alongside the BRAF V600E mutation. Subsequent liquid biopsy after liver recurrence confirmed the persistence of the KRAS Q61H mutation. Our results highlight the significance of cancer genome profiling tests (CGP tests) and liquid biopsies in guiding treatment strategies for BRAF-mutant colorectal cancer. Therefore, CGP testing offers valuable information for treatment, even if it does not lead to new drug administrations.

Gut microbiota characteristics of colorectal cancer patients in Hubei, China, and differences with cohorts from other Chinese regions.

The research on the correlation or causality between gut microbiota and the occurrence, development, and treatment of colorectal cancer (CRC) is receiving increasing emphasis. At the same time, the incidence and mortality of colorectal cancer vary among individuals and regions, as does the gut microbiota. In order to gain a better understanding of the characteristics of the gut microbiota in CRC patients and the differences between different regions, we initially compared the gut microbiota of 25 CRC patients and 26 healthy controls in the central region of China (Hubei Province) using 16S rRNA high-throughput sequencing technology. The results showed that Corynebacterium, Enterococcus, Lactobacillus, and Escherichia-Shigella were significantly enriched in CRC patients. In addition, we also compared the potential differences in functional pathways between the CRC group and the healthy control group using PICRUSt's functional prediction analysis. We then analyzed and compared it with five cohort studies from various regions of China, including Central, East, and Northeast China. We found that geographical factors may affect the composition of intestinal microbiota in CRC patients. The composition of intestinal microbiota is crucial information that influences colorectal cancer screening, early detection, and the prediction of CRC treatment outcomes. This emphasizes the importance of conducting research on CRC-related gut microbiota in various regions of China.

Prognostic impact of myosteatosis in patients with colorectal cancer undergoing curative surgery: an updated systematic review and meta-analysis.

Background: Colorectal cancer (CRC) is a global health concern, and identifying prognostic factors can improve outcomes. Myosteatosis is fat infiltration into muscles and is a potential predictor of the survival of patients with CRC. Methods: This systematic review and meta-analysis aimed to assess the prognostic role of myosteatosis in CRC. PubMed, Embase, and Cochrane CENTRAL were searched up to 1 August 2023, for relevant studies, using combinations of the keywords CRC, myosteatosis, skeletal muscle fat infiltration, and low skeletal muscle radiodensity. Case-control, prospective, and retrospective cohort studies examining the association between myosteatosis and CRC outcomes after curative intent surgery were eligible for inclusion. Primary outcomes were overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS). Results: A total of 10 studies with a total of 9,203 patients were included. The pooled hazard ratio (HR) for OS (myosteatosis vs. no myosteatosis) was 1.52 [95% confidence interval (CI), 1.38-1.67); for CSS, 1.67 (95% CI, 1.40-1.99); and for DFS, 1.89 (95% CI, 1.35-2.65). Conclusion: In patients with CRC undergoing curative intent surgery, myosteatosis is associated with worse OS, CSS, and DFS. These findings underscore the importance of evaluating myosteatosis in patients with CRC to improve outcomes.

Elucidating the role of angiogenesis-related genes in colorectal cancer: a multi-omics analysis.

Background: Angiogenesis plays a pivotal role in colorectal cancer (CRC), yet its underlying mechanisms demand further exploration. This study aimed to elucidate the significance of angiogenesis-related genes (ARGs) in CRC through comprehensive multi-omics analysis. Methods: CRC patients were categorized according to ARGs expression to form angiogenesis-related clusters (ARCs). We investigated the correlation between ARCs and patient survival, clinical features, consensus molecular subtypes (CMS), cancer stem cell (CSC) index, tumor microenvironment (TME), gene mutations, and response to immunotherapy. Utilizing three machine learning algorithms (LASSO, Xgboost, and Decision Tree), we screen key ARGs associated with ARCs, further validated in independent cohorts. A prognostic signature based on key ARGs was developed and analyzed at the scRNA-seq level. Validation of gene expression in external cohorts, clinical tissues, and blood samples was conducted via RT-PCR assay. Results: Two distinct ARC subtypes were identified and were significantly associated with patient survival, clinical features, CMS, CSC index, and TME, but not with gene mutations. Four genes (S100A4, COL3A1, TIMP1, and APP) were identified as key ARCs, capable of distinguishing ARC subtypes. The prognostic signature based on these genes effectively stratified patients into high- or low-risk categories. scRNA-seq analysis showed that these genes were predominantly expressed in immune cells rather than in cancer cells. Validation in two external cohorts and through clinical samples confirmed significant expression differences between CRC and controls. Conclusion: This study identified two ARG subtypes in CRC and highlighted four key genes associated with these subtypes, offering new insights into personalized CRC treatment strategies.

Impact of Circular Stapler Size on the Risk of Anastomotic Complications in Patients With Left-sided Colorectal Cancer: A Propensity Score-matched Study.

Background/Aim: The present study examined the impact of circular stapler size on anastomotic complications, including leakage and stricture in patients undergoing double-stapling technique (DST) anastomosis for left-sided colon or rectal cancer. Patients and Methods: A total of 403 patients were enrolled in this study, with circular stapler sizes  of 25, 28, and 29 mm. Results: A small circular stapler (25 mm) was used in 170 cases (42.2%), and a medium-sized circular stapler (28/29 mm) was used in 233 cases (57.8%). After propensity score matching, there was no marked difference in the incidence of anastomotic leakage/stricture between the groups (13.9% vs. 10.9%, 3.0% vs. 1.0%, respectively). Conclusion: The size of the circular stapler was not associated with the incidence of anastomotic leakage or stricture in this cohort.

BMP Signaling Is a Prognostic Marker in Patients With Colorectal Cancer and Associates With Frailty.

Background/Aim: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-ß superfamily of ligands and have been shown to promote or suppress colorectal cancer (CRC) growth. Developing treatments that target BMPs is challenging due to their multiple roles, including involvement in the inflammatory response and nutritional status. The present study evaluated the prognostic value of BMP-4, which is believed to be highly expressed in CRC, and its correlation with inflammatory and nutrition statuses in patients with CRC. Materials and Methods: We analyzed BMP-4 expression in tumor tissues from 144 patients who underwent CRC surgery using immunohistochemistry and evaluated the relationship between BMP-4 levels and clinical outcomes. Results: Kaplan-Meier analysis revealed that patients with high expression levels of BMP-4 exhibited a shorter overall survival rate than those with low levels of expression. Multivariate analysis revealed that BMP-4 expression was an independent prognostic factor for overall survival and death from other diseases in CRC patients. Furthermore, high BMP-4 expression was significantly correlated with high C-reactive protein/Albumin ratio, sarcopenia, and osteopenia. Conclusion: BMP-4 is a significant prognostic factor in CRC, particularly in predicting death from other diseases, while also showing associations with inflammatory and nutritional statuses.

Racial disparities in colorectal cancer outcomes and access to care: a multi-cohort analysis.

Introduction: Non-Hispanic Black (NHB) Americans have a higher incidence of colorectal cancer (CRC) and worse survival than non-Hispanic white (NHW) Americans, but the relative contributions of biological versus access to care remain poorly characterized. This study used two nationwide cohorts in different healthcare contexts to study health system effects on this disparity. Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) registry as well as the United States Veterans Health Administration (VA) to identify adults diagnosed with colorectal cancer between 2010 and 2020 who identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW). Stratified survival analyses were performed using a primary endpoint of overall survival, and sensitivity analyses were performed using cancer-specific survival. Results: We identified 263,893 CRC patients in the SEER registry (36,662 (14%) NHB; 226,271 (86%) NHW) and 24,375 VA patients (4,860 (20%) NHB; 19,515 (80%) NHW). In the SEER registry, NHB patients had worse OS than NHW patients: median OS of 57 months (95% confidence interval (CI) 55-58) versus 72 months (95% CI 71-73) (hazard ratio (HR) 1.14, 95% CI 1.12-1.15, p = 0.001). In contrast, VA NHB median OS was 65 months (95% CI 62-69) versus NHW 69 months (95% CI 97-71) (HR 1.02, 95% CI 0.98-1.07, p = 0.375). There was significant interaction in the SEER registry between race and Medicare age eligibility (p < 0.001); NHB race had more effect in patients <65 years old (HR 1.44, 95% CI 1.39-1.49, p < 0.001) than in those ≥65 (HR 1.13, 95% CI 1.11-1.15, p < 0.001). In the VA, age stratification was not significant (p = 0.21). Discussion: Racial disparities in CRC survival in the general US population are significantly attenuated in Medicare-aged patients. This pattern is not present in the VA, suggesting that access to care may be an important component of racial disparities in this disease.

Jianpi Jiedu decoction suppresses colorectal cancer growth by inhibiting M2 polarization of TAMs through the tryptophan metabolism-AhR pathway.

BACKGROUND: Traditional Chinese medicine, JianpiJiedu decoction (JPJDF), has been utilized in colorectal cancer (CRC) treatment for over forty years. The potential of JPJDF to inhibit CRC through modulation of intestinal microbiota and their metabolites remains uncertain. AIMS: This study aims to further investigate the therapeutic mechanisms of JPJDF in CRC. METHODS: CAC mouse models were developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissues and contents underwent 16S rRNA gene sequencing and untargeted metabolomics analysis. Serum levels of IL-1ß and TNF-α were measured using ELISA. Immunohistochemistry was utilized to assess the expression of Ki67, ZO-1, Occludin, CD68, and CD206. Furthermore, western blotting was performed to evaluate the protein expression of AhR and NF-κB. RESULTS: JPJDF inhibited colorectal tumourigenesis in AOM/DSS treated mice, while also suppressing tumor cell proliferation and upregulating the expression of tight junction proteins. The results of 16S rRNA gene sequencing analysis revealed that JPJDF altered intestinal microbiota composition by increasing the abundance of beneficial bacteria. Additionally, JPJDF reduced tryptophan metabolites, effectively alleviating inflammation and significantly restoring intestinal barrier function in CAC mice. Molecular biology experiments confirmed that JPJDF suppressed the expression levels of AhR and M2-type tumor-associated macrophages, thereby promoting anti-tumor immunity and exerting inhibitory effects on CAC growth. CONCLUSION: JPJDF can regulate the tryptophan metabolism-AhR pathway by modulating the gut microbiota, reducing intestinal inflammation, improving intestinal barrier function, enhancing anti-tumor immunity, and effectively inhibiting CAC growth.

Transformers for colorectal cancer segmentation in CT imaging.

PURPOSE: Most recently transformer models became the state of the art in various medical image segmentation tasks and challenges, outperforming most of the conventional deep learning approaches. Picking up on that trend, this study aims at applying various transformer models to the highly challenging task of colorectal cancer (CRC) segmentation in CT imaging and assessing how they hold up to the current state-of-the-art convolutional neural network (CNN), the nnUnet. Furthermore, we wanted to investigate the impact of the network size on the resulting accuracies, since transformer models tend to be significantly larger than conventional network architectures. METHODS: For this purpose, six different transformer models, with specific architectural advancements and network sizes were implemented alongside the aforementioned nnUnet and were applied to the CRC segmentation task of the medical segmentation decathlon. RESULTS: The best results were achieved with the Swin-UNETR, D-Former, and VT-Unet, each transformer models, with a Dice similarity coefficient (DSC) of 0.60, 0.59 and 0.59, respectively. Therefore, the current state-of-the-art CNN, the nnUnet could be outperformed by transformer architectures regarding this task. Furthermore, a comparison with the inter-observer variability (IOV) of approx. 0.64 DSC indicates almost expert-level accuracy. The comparatively low IOV emphasizes the complexity and challenge of CRC segmentation, as well as indicating limitations regarding the achievable segmentation accuracy. CONCLUSION: As a result of this study, transformer models underline their current upward trend in producing state-of-the-art results also for the challenging task of CRC segmentation. However, with ever smaller advances in total accuracies, as demonstrated in this study by the on par performances of multiple network variants, other advantages like efficiency, low computation demands, or ease of adaption to new tasks become more and more relevant.

Molecular Understanding and Pharmacological Potency of Plant-Derived Compounds in Colorectal Cancer (CRC): A Critical Analysis and Future Perspectives.

Colorectal cancer (CRC) is the main driver of fatality and the 3rd most often determined malignancy. Despite advances in detection and therapy, colorectal cancer (CRC) endures as the largest driver of cancer-related morbidity, and mortality. Modern habits and dietary negligence might be one of the reasons that have enhanced cancer prevalence. Thus, changes in Dietary habits will have a better impact, and help in finding a better cure for CRC. Initially, CRC was explored as a genetic event and currently, the research is focused on the epigenetic modifications of chromatin and microRNA (miRNA) in CRC cells. Natural products such as Curcumin, Resveratrol, Flavonoids, and Ellagitannins are been explored as compounds from the perspective of genetic, epigenetic, and miRNA modifications which will have future therapeutic aspects. Also, the extracts of these key players and their analogs will intervene the signaling pathway activation that involves in cancer propagation, apoptosis, cell cycle arrest, and epigenetic and miRNA modifications. Modulations of these miRNAs, and modification globally might have impact on CRC progression, and cancer tumor cell sensitivity.

Serum biomarkers REG1A and REG3A combined with the traditional CEA represent a novel nomogram for the screening and risk stratification of colorectal cancer.

BACKGROUND: To develop and validate a serum protein nomogram for colorectal cancer (CRC) screening. METHODS: The serum protein characteristics were extracted from an independent sample containing 30 colorectal cancer and 12 polyp tissues along with their paired samples, and different serum protein expression profiles were validated using RNA microarrays. The prediction model was developed in a training cohort that included 1345 patients clinicopathologically confirmed CRC and 518 normal participants, and data were gathered from November 2011 to January 2017. The lasso logistic regression model was employed for features selection and serum nomogram building. An internal validation cohort containing 576 CRC patients and 222 normal participants was assessed. RESULTS: Serum signatures containing 27 secreted proteins were significantly differentially expressed in polyps and CRC compared to paired normal tissue, and REG family proteins were selected as potential predictors. The C-index of the nomogram1 (based on Lasso logistic regression model) which contains REG1A, REG3A, CEA and age was 0.913 (95% CI, 0.899 to 0.928) and was well calibrated. Addition of CA199 to the nomogram failed to show incremental prognostic value, as shown in nomogram2 (based on logistic regression model). Application of the nomogram1 in the independent validation cohort had similar discrimination (C-index, 0.912 [95% CI, 0.890 to 0.934]) and good calibration. The decision curve (DCA) and clinical impact curve (ICI) analysis demonstrated that nomogram1 was clinically useful. CONCLUSIONS: This study presents a serum nomogram that included REG1A, REG3A, CEA and age, which can be convenient for screening of colorectal cancer.

Non B Cell-Derived Immunoglobulins in Intestinal Tract.

Intestinal epithelium constitutes a barrier to the unrestricted movement of pathogens, and other detrimental substances from the external world (gut lumen) into the interstitial environment. Intestinal epithelial cells obstruct harmful substances passing through the epithelium as a physical and chemical barrier; Moreover, the epithelial cells can express Toll-like receptors (TLRs) and cytokines to exert innate immune function. In addition, high levels of immunoglobulin A (IgA) and other antibodies exist in the intestinal mucosa, maintaining intestinal immune homeostasis in conjunction with intestinal probiotics. Traditionally, these antibodies have been deemed to be secreted by submucosal plasma cells. Nonetheless, in recent years, it has been demonstrated that intestinal epithelial cells produce a substantial amount of Igs, especially IgA or free Ig light chains, which are involved in intestinal immune homeostasis and the survival of normal epithelial cells. Furthermore, mounting evidence affirms that many human carcinoma cells, including colorectal cancer (CRC), can overexpress Igs, particularly IgG. Cancer-derived Igs exhibit a unique V(D)J rearrangement pattern distinct from B cell-derived Ig; moreover, this cancer cell-derived IgG also has a unique sialic acid modification on the 162 site of CH1 domain (SIA-IgG). The SIA-IgG plays a crucial role in promoting cancer initiation, progression, metastasis, and tumour immune escape. Simultaneously, CRC cells can also express free Ig light chains, which promote colitis, colitis-associated colon carcinogenesis, and CRC progression. Therefore, Igs expressed by CRC cells could be a potential target for diagnosing and preventing the transformation of inflammation into cancer, as well as treating CRC.

Notopterygium Incisum Extract Promotes Apoptosis by Preventing the Degradation of BIM in Colorectal Cancer.

OBJECTIVE: Colorectal cancer (CRC), a prevalent malignancy worldwide, has prompted extensive research into anticancer drugs. Traditional Chinese medicinal materials offer promising avenues for cancer management due to their diverse pharmacological activities. This study investigated the effects of Notopterygium incisum, a traditional Chinese medicine named Qianghuo (QH), on CRC cells and the underlying mechanism. METHODS: The sulforhodamine B assay and colony formation assay were employed to assess the effect of QH extract on the proliferation of CRC cell lines HCT116 and Caco-2. Propidium iodide (PI) staining was utilized to detect cell cycle progression, and PE Annexin V staining to detect apoptosis. Western blotting was conducted to examine the levels of apoptotic proteins, including B-cell lymphoma 2-interacting mediator of cell death (BIM), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (BAX) and cleaved caspase-3, as well as BIM stability after treatment with the protein synthesis inhibitor cycloheximide. The expression of BAX was suppressed using lentivirus-mediated shRNA to validate the involvement of the BIM/BAX axis in QH-induced apoptosis. The in vivo effects of QH extract on tumor growth were observed using a xenograft model. Lastly, APCMin+ mice were used to study the effects of QH extract on primary intestinal tumors. RESULTS: QH extract exhibited significant in vitro anti-CRC activities evidenced by the inhibition of cell proliferation, perturbation of cell cycle progression, and induction of apoptosis. Mechanistically, QH extract significantly increased the stability of BIM proteins, which undergo rapid degradation under unstressed conditions. Knockdown of BAX, the downstream effector of BIM, significantly rescued QH-induced apoptosis. Furthermore, the in vitro effect of QH extract was recapitulated in vivo. QH extract significantly inhibited the tumor growth of HCT116 xenografts in nude mice and decreased the number of intestinal polyps in the APCMin+ mice. CONCLUSION: QH extract promotes the apoptosis of CRC cells by preventing the degradation of BIM.

Tumour-associated and non-tumour-associated bacteria co-abundance groups in colorectal cancer.

BACKGROUND & AIMS: Gut microbiota is closely related to the occurrence and development of colorectal cancer (CRC). However, the differences in bacterial co-abundance groups (CAGs) between tumor tissue (TT) and normal tissue (NT), as well as their associations with clinical features, are needed to be clarified. METHODS: Bacterial 16 S rRNA sequencing was performed by using TT samples and NT samples of 251 patients with colorectal cancer. Microbial diversity, taxonomic characteristics, microbial composition, and functional pathways were compared between TT and NT. Hierarchical clustering was used to construct CAGs. RESULTS: Four CAGs were grouped in the hierarchical cluster analysis. CAG 2, which was mainly comprised of pathogenic bacteria, was significantly enriched in TT samples (2.27% in TT vs. 0.78% in NT, p < 0.0001). CAG 4, which was mainly comprised of non-pathogenic bacteria, was significantly enriched in NT samples (0.62% in TT vs. 0.79% in NT, p = 0.0004). In addition, CAG 2 was also significantly associated with tumor microsatellite instability (13.2% in unstable vs. 2.0% in stable, p = 0.016), and CAG 4 was positively correlated with the level of CA199 (r = 0.17, p = 0.009). CONCLUSIONS: Our research will deepen our understanding of the interactions among multiple bacteria and offer insights into the potential mechanism of NT to TT transition.

E3 ubiquitin ligase RNF128 attenuates colitis and colorectal tumorigenesis by triggering the degradation of IL-6 receptors.

INTRODUCTION: Intestinal immune dysregulation is strongly linked to the occurrence and formation of tumors. RING finger protein 128 (RNF128) has been identified to play distinct immunoregulatory functions in innate and adaptive systems. However, the physiological roles of RNF128 in intestinal inflammatory conditions such as colitis and colorectal cancer (CRC) remain controversial. OBJECTIVES: To elucidate the function and mechanism of RNF128 in colitis and CRC. METHODS: Animal models of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced CRC were established in WT and Rnf128-deficient mice and evaluated by histopathology. Co-immunoprecipitation and ubiquitination analyses were employed to investigate the role of RNF128 in IL-6-STAT3 signaling. RESULTS: RNF128 was significantly downregulated in clinical CRC tissues compared with paired peritumoral tissues. Rnf128-deficient mice were hypersusceptible to both colitis induced by DSS and CRC induced by AOM/DSS or APC mutation. Loss of RNF128 promoted the proliferation of CRC cells and STAT3 activation during the early transformative stage of carcinogenesis in vivo and in vitro when stimulated by IL-6. Mechanistically, RNF128 interacted with the IL-6 receptor α subunit (IL-6Rα) and membrane glycoprotein gp130 and mediated their lysosomal degradation in ligase activity-dependent manner. Through a series of point mutations in the IL-6 receptor, we identified that RNF128 promoted K48-linked polyubiquitination of IL-6Rα at K398/K401 and gp130 at K718/K816/K866. Additionally, blocking STAT3 activation effectively eradicated the inflammatory damage of Rnf128-deficient mice during the transformative stage of carcinogenesis. CONCLUSION: RNF128 attenuates colitis and colorectal tumorigenesis by inhibiting IL-6-STAT3 signaling, which sheds novel insights into the modulation of IL-6 receptors and the inflammation-to-cancer transition.

Quality of endoscopic surveillance of Lynch syndrome patients in a Swedish cohort.

Background and study aims Risk factors for colorectal cancer (CRC) in Lynch syndrome (LS) include sex, age, smoking, high body mass index (BMI), surveillance interval length, and risk genotype. The Boston Bowel Preparation Scale (BBPS) produces a standardized bowel cleanliness rating. A low BBPS score might be a risk factor for missed early lesions. The aim of this study was to investigate the correlation between BBPS score and adenoma detection (with known risk factors for CRC) and surveillance interval with CRC detection in LS patients. Methods A retrospective cohort study including 366 LS patients with 1,887 colonoscopies under surveillance in Stockholm, Sweden from 1989 to 2021 was conducted. Associations were tested using linear and logistic regression. Results We found no association between BBPS score and number of adenomas detected. A low BBPS score was found to be associated with older age (regression coefficient (coeff) -0.015; 95% confidence interval [CI] -0.026 to -0.004; P = 0.007) and obesity (coeff = -0.48; 95% CI: -0.89 to -0.062; P = 0.024). A higher number of detected adenomas was associated with older age (coeff = 0.008; 95% CI 0.004 to 0.012; P < 0.001), male sex (coeff = 0.097; 95% CI 0.008 to 0.19; P = 0.033) and CRC (coeff = 0.28; 95% CI 0.061 to 0.50; P = 0.012). Surveillance interval length was not significant in CRC detection. Conclusions Bowel cleanliness was not associated with adenoma detection and was less likely achieved in patients who were older and had higher BMI. Adenoma detection was associated with older age and male sex. The results indicate the need for better adherence to guidelines and attention to older age groups, men, and patients with obesity.

Proteomic insights into the regulatory function of ARID1A in colon cancer cells.

The AT-rich interacting domain-containing protein 1A (ARID1A) is a tumor suppressor gene that has been implicated in several cancers, including colorectal cancer (CRC). The present study used a proteomic approach to elucidate the molecular mechanisms of ARID1A in CRC carcinogenesis. Stable ARID1A-overexpressing SW48 colon cancer cells were established using lentivirus transduction and the successful overexpression of ARID1A was confirmed by western blotting. Label-free quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry identified 705 differentially altered proteins in the ARID1A-overexpressing cells, with 310 proteins significantly increased and 395 significantly decreased compared with empty vector control cells. Gene Ontology enrichment analysis highlighted the involvement of the altered proteins mainly in the Wnt signaling pathway. Western blotting supported these findings, as a decreased protein expression of Wnt target genes, including c-Myc, transcription factor T cell factor-1/7 and cyclin D1, were observed in ARID1A-overexpressing cells. Among the altered proteins involved in the Wnt signaling pathway, the interaction network analysis revealed that ARID1A exhibited a direct interaction with E3 ubiquitin-protein ligase zinc and ring finger 3 (ZNRF3), a negative regulator of the Wnt signaling pathway. Further analyses using the The Cancer Genome Atlas colon adenocarcinoma public dataset revealed that ZNRF3 expression significantly impacted the overall survival of patients with CRC and was positively correlated with ARID1A expression. Finally, an increased level of ZNRF3 in ARID1A-overexpressing cells was confirmed by western blotting. In conclusion, the findings of the present study suggest that ARID1A negatively regulates the Wnt signaling pathway through ZNRF3, which may contribute to CRC carcinogenesis.

Global incidence trends of early-onset colorectal cancer and related exposures in early-life: an ecological analysis based on the GBD 2019.

Background: The incidence of early-onset colorectal cancer (EOCRC) is increasing globally. This study aims to describe the temporal trends of incidence and explore related risk exposures in early-life at the country level based on the GBD 2019. Methods: Data on the incidence and attributable risk factors of EOCRC were obtained from the GBD 2019. Temporal trends of age-standardized incidence were evaluated by average annual percentage change (AAPC). Early-life exposures were indicated as summary exposure values (SEV) of selected factors, SDI and GDP per capita in previous decades and at ages 0-4, 5-9, 10-14 and 15-19 years. Weighted linear or non-linear regressions were applied to evaluate the ecological aggregate associations of the exposures with incidences of EOCRC. Results: The global age-standardized incidence of EOCRC increased from 3.05 (3.03, 3.07) to 3.85 (3.83, 3.86) per 100,000 during 1990 and 2019. The incidence was higher in countries with high socioeconomic levels, and increased drastically in countries in East Asia and Caribbean, particularly Jamaica, Saudi Arabia and Vietnam. The GDP per capita, SDI, and SEVs of iron deficiency, alcohol use, high body-mass index, and child growth failure in earlier years were more closely related with the incidences of EOCRC in 2019. Exposures at ages 0-4, 5-9, 10-14 and 15-19 years were also associated with the incidences, particularly for the exposures at ages 15-19 years. Conclusion: The global incidence of EOCRC increased during past three decades. The large variations at regional and national level may be related with the distribution of risk exposures in early life.

Piperine induces autophagy of colon cancer cells: Dual modulation of AKT/mTOR signaling pathway and ROS production.

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy and poses a significant clinical challenge. Piperine, an alkaloid molecule extracted from Piper nigrum and Piper longum, has emerged as a promising anticancer agent. However, the molecular mechanisms of piperine' antitumor effects in CRC need to be further elucidated. METHODS: Human colorectal cancer cells were treated with piperine in vitro. CCK-8 and clone formation assays were adopted to detect cell viability. The accumulation of autophagosomes was assessed by Western blotting and immunofluorescence. Apoptosis and reactive oxygen species (ROS) levels were analyzed by flow. In vivo, a xenograft tumor mouse model was constructed using CT26 cells. RESULTS: Piperine inhibited CRC cell viability and suppressed tumor weight and volume in a mouse model. Additionally, piperine treatment induced the accumulation of autophagosomes in CRC cells. This effect was attributed to the inhibition of the AKT/mTOR pathway and the accumulation of ROS. activation of AKT or clearance of ROS attenuated piperine-mediated tumor suppression. CONCLUSION: This study shows that piperine induces autophagy-dependent cell death in CRC cells by increasing ROS production and inhibiting Akt/mTOR signaling.