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We have investigated the role of MSH2, a mismatch repair gene in cell proliferation, cell cycle control and cell invasiveness in the SW480 human colorectal cancer cell line. RNAi-mediated inhibition of MSH2 expression was achieved using MSH2 shRNA lentiviral expression vectors. Effective knockdown of endogenous MSH2 expression was determined by real-time PCR analysis. The most efficient MSH2 knockdown vector was selected for subsequent studies using SW480 cells. Endogenous MSH2 mRNA levels decreased after lentiviral delivery of the MSH2-RNAi, indicating efficient silencing of MSH2 expression in SW480 cells. Cell proliferation, cell cycle progression and cell invasiveness were quantified by MTT assays, flow cytometry and transwell assays, respectively. RNAi-mediated inhibition of MSH2 expression in SW480 cells resulted in decreased cell proliferation, cell cycle arrest at the G0/G1 phase and decreased cell invasiveness. Taken together, these results provide evidence that MSH2 stimulates cell proliferation, promotes cell cycle progression and positively regulates cell invasiveness. [ABSTRACT FROM AUTHOR]

Abstract: Background: Several studies have shown that metabolic syndrome (MS) was a risk factor for colorectal cancer, but few studies have reported the relationship between MS and the prognosis of colorectal cancer. Methods: Data were collected from 507 cases of colorectal carcinoma between January 2002 and March 2007 to establish the database. These patients were divided into 2 groups based on the presence of MS. We tested the prognostic value of MS in the patients. The risk of adverse events was examined by Cox proportional hazard modeling. Results: The rates of liver metastasis and tumor recurrence were higher in the group of patients with colorectal cancer accompanied by MS. Moreover, MS is one of the important elements that independently can influence the survival (colonic carcinoma: hazard ratio [HR], 1.633; 95% confidence interval [CI], 1.039–2.565; rectal carcinoma: HR, 1.939, 95% CI, 1.076–3.494) and liver metastasis (colonic carcinoma: HR, 2.619; 95% CI, 1.288–5.324; rectal carcinoma: HR, 2.814; 95% CI, .962–2.888) of both colonic and rectal carcinoma patients, and MS patients have the highest risk with worse survival and liver metastases compared with other parameters. Conclusions: The results suggest that MS may be an important prognostic factor for colorectal cancer, decreasing the incidence of MS may improve the therapeutic efficacy of colorectal cancer. [Copyright &y& Elsevier]

Colorectal cancer (CRC) is the third most prevalent and second most lethal cancer globally, with gene mutations and tumor metastasis contributing to its poor prognosis. Single-cell sequencing technology enables high-throughput analysis of the genome, transcriptome, and epigenetic landscapes at the single-cell level. It offers significant insights into analyzing the tumor immune microenvironment, detecting tumor heterogeneity, exploring metastasis mechanisms, and monitoring circulating tumor cells (CTCs). This article provides a brief overview of the technical procedure and data processing involved in single-cell sequencing. It also reviews the current applications of single-cell sequencing in CRC research, aiming to enhance the understanding of intratumoral heterogeneity, CRC development, CTCs, and novel drug targets. By exploring the diverse molecular and clinicopathological characteristics of tumor heterogeneity using single-cell sequencing, valuable insights can be gained into early diagnosis, therapy, and prognosis of CRC. Thus, this review serves as a valuable resource for identifying prognostic markers, discovering new therapeutic targets, and advancing personalized therapy in CRC. [ABSTRACT FROM AUTHOR]

Background: We performed this study to identify predictive factors for lymph node metastasis (LNM) and analyze the impact of LNM on the prognosis of patients with T1-2 colorectal cancer (CRC), with the intention of providing guidance for the treatment. Methods: The Surveillance Epidemiology and End Result database was used to identify 20,492 patients diagnosed with T1-2 stage CRC between 2010 and 2019, who underwent surgery and lymph node evaluation and had complete prognostic information. Clinicopathological data of patients with T1-2 stage colorectal cancer treated with surgery at Peking University People's Hospital from 2017 to 2021 with complete clinical information were retrieved. We identify and confirm the risk factors for positive lymph node involvement, and the results of follow-up were analyzed. Results: Age, preoperative carcinoembryonic antigen (CEA) level, perineural invasion, and primary tumor site were independent risk factors for LNM in T1-2 CRC based on the analysis of the SEER database, while tumor size and histology of mucinous carcinoma were also independent risk factors in T1 CRC. We then make the nomogram model for predicting LNM risk and showed an acceptable consistency and calibration capability. Survival analysis showed that LNM was an independent prognostic indicator of 5-year disease-specific survival (P = 0.013) and disease-free survival (P < 0.001) in patients with T1 and T2 CRC. Conclusion: Age, CEA level and primary tumor site should be taken into consideration before making the surgical decision in T1-2 CRC patients. The tumor size and histology of mucinous carcinoma also need to be thought about in T1 CRC. Conventional imaging tests do not appear to provide a precise assessment for this issue. [ABSTRACT FROM AUTHOR]

The biological role of the spen paralogue and orthologue C-terminal domain containing 1 (SPOCD1) has been investigated in human malignancies, but its function in colorectal cancer (CRC) is unclear. This study investigated the association between SPOCD1 expression and clinicopathological features of CRC cases, as well as its prognostic value and biological function based on large-scale databases and clinical samples. The results showed that the expression level of SPOCD1 was elevated in CRC, which was generally associated with shortened survival time and poor clinical indexes, including advanced T, N, and pathologic stages. Multivariate Cox regression analysis showed that elevated SPOCD1 expression was an independent factor for poor prognosis in CRC patients. Functional enrichment analysis of SPOCD1 and its co-expressed genes revealed that SPOCD1 could act as an oncogene by regulating gene expression in essential functions and pathways of tumorigenesis, such as extracellular matrix organization, chemokine signaling pathways, and calcium signaling pathways. In addition, immune cell infiltration results showed that SPOCD1 expression was associated with various immune cells, especially macrophages. Furthermore, our findings suggested a possible function for SPOCD1 in the polarization of macrophages from M1 to M2 in CRC. In conclusion, SPOCD1 is a promising diagnostic and prognostic marker for CRC, opening new avenues for research and treatment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate a new strategy for profiling proteomic changes in colorectal cancer (CRC). Methodes: We used laser capture microdissection (LCM) to obtain cells from 20 CRC and paired normal mucosal tissues. The differential proteins between the microdissected tumor cells and normal mucosa epithelia were analyzed by acetylation stable isotopic labeling coupled with L linear ion trap Fourier transform ion cyclotron resonance mass spectrometry (LTQ-FT MS). Western blotting was used to assess the differential expression of proteins. We used bioinformatics tools for cluster and ingenuity pathway analysis of the differential proteins. Results: In total, 798 confident proteins were quantified and 137 proteins were differentially expressed by at least twofold, including 67 that were upregulated and 70 that were downregulated in cancer. Two differential proteins, solute carrier family 12 member 2 (SLC12A2) and Ras-related protein Rab-10, were validated by Western blotting, and the results were consistent with acetylation stable isotopic labeling analysis. According to gene ontology analysis, CRC-related differential proteins covered a wide range of subcellular locations and were involved in many biological processes. According to ingenuity pathway analysis of the differential proteins, the most relevant canonical pathway associated with CRC was the 14-3-3-mediated signaling pathway, and seven reliable functional networks including cellular growth and proliferation, amino acid metabolism, inflammatory response, embryonic development, carbohydrate metabolism, cellular assembly and organization, and cell morphology were obtained. Conclusions: Combination of LCM, acetylation stable isotopic labeling analysis and LTQ-FT MS is effective for profiling proteomic changes in CRC cells. [ABSTRACT FROM AUTHOR]

Background: As the most widespread mRNAs modification, N6‐methyladenosine (m6A) is dynamically and reversibly modulated by methyltransferases and demethylases. ALKBH5 is a major demethylase, and plays vital roles in the progression of cancers. However, the role and mechanisms of ALKBH5 in colorectal cancer (CRC) is unclear. Results: Herein, we discovered that in CRC, downregulated ALKBH5 was closely related to poor prognosis of CRC patients. Functionally, our results demonstrated that knockdown of ALKBH5 enhanced the proliferation, migration and invasion of LOVO and RKO in vitro, while overexpression of ALKBH5 inhibited the functions of these cells. The results also demonstrated that knockdown of ALKBH5 promoted subcutaneous tumorigenesis of LOVO in vivo, while overexpression of ALKBH5 suppressed this ability. Mechanistically, results from joint analyses of MeRIP‐seq and RNA‐seq indicated that PHF20 mRNA was a key molecule that was regulated by ALKBH5‐mediated m6A modification. Further experiments indicated that ALKBH5 may inhibit stability of PHF20 mRNA by removing the m6A modification of PHF20 mRNA 3′UTR. Conclusions: ALKBH5 suppresses CRC progression by decreasing PHF20 mRNA methylation. ALKBH5‐mediated m6A modification of PHF20 mRNA can serve as a hopeful strategy for the intervention and treatment of CRC. [ABSTRACT FROM AUTHOR]

Standard treatment of colorectal cancer (CRC) improves the prognosis of CRC patients, but it is still intractable to control the progression of metastatic CRC. Immune microenvironment and immunotherapies of CRC have received extensive attention in recent years, but present immunotherapies of CRC have mainly focused on T cells and therapeutic response is only observed in a small proportion of patients. Innate immune cells are the first-line of defense in the development of malignancies. Natural killer (NK) cells, NKT cells and γδT cells are three types of innate cells of lymphoid origin and show cytotoxicity against various tumor cells including CRC. Besides, in the development of CRC, they can also be inhibited or express regulatory type, promoting tumor progression. Researches about anti-tumorigenic and pro-tumorigenic mechanisms of these cells are ongoing and regulation of these cells is also being unearthed. Meanwhile, immunotherapies using these cells more or less have shown efficacy in animal models and some of them are under exploration in clinical trials. This review provides an overview of intrinsic properties of NK cell, NKT cell and γδT cell, and summarizes current related promising treatment strategies. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the prognostic value and staging accuracy of the metastatic lymph node ratio (rN) staging system for colorectal cancer. Methods: A total of 1,127 patients with colorectal cancer who underwent curative surgery between 2000 and 2011 at our institute were analyzed. Lymph nodes status was assigned according to American Joint Committee on Cancer (AJCC) pN system and rN system. Patients with colon cancer (group 1, n = 652) and rectal cancer (group 2, n = 475) were analyzed separately. Results: The rN staging system was generated using 0.2 and 0.6 as the cutoff values of lymph node ratio and then compared with AJCC pN stages. Linear regression model revealed that the number of retrieved lymph node was related to number of metastatic lymph nodes. After a median follow-up of 46 months, the 5-year survival rates of patients with more than 12 lymph nodes (LNs) retrieved were better than cases with fewer than 12 LNs, while the differences were not obvious in rN classification. Conclusions : The rN category is a better prognostic tool than the AJCC pN category for colorectal cancer patients after curative surgery. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) have emerged as vital regulators of the initiation and progression of diverse kinds of human cancers. In this study, we explored the role of hsa_circ_0000231 and its downstream pathway in CRC. Methods: The expression profile of circRNAs in 5 pairs of CRC tissues and adjacent normal tissues were analyzed by Microarray. Quantitative real-time PCR and in situ hybridization and Base Scope Assay were used to determine the level and prognostic values of hsa_circ_0000231. Then, functional experiments in vitro and in vivo were performed to investigate the effects of hsa_circ_0000231 on cell proliferation. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between hsa_circ_0000231 and IGF2BP3 or has_miR-375. Results: We acquired data through circRNA microarray profiles, showing that the expression of hsa_circ_0000231 was upregulated in CRC primary tissues compared to adjacent normal tissues, which was indicated poor prognosis of patients with CRC. Functional analysis indicated that inhibition of hsa_circ_0000231 in CRC cell lines could suppress CRC cell proliferation as well as tumorigenesis in vitro and in vivo. The mechanistic analysis showed that hsa_circ_0000231 might, on the one hand, act as a competing endogenous RNA of miR-375 to promote cyclin D2 (CCND2) and, on the other hand, bind to the IGF2BP3 protein to prevent CCND2 degradation. Conclusions: The findings suggested that hsa_circ_0000231 facilitated CRC progression by sponging miR-375 or binding to IGF2BP3 to modulate CCND2, implying that hsa_circ_0000231 might be a potential new diagnostic and therapeutic biomarker of CRC. [ABSTRACT FROM AUTHOR]

Objective: Postoperative bowel obstruction was one of the most severe complications in patients who received colorectal surgeries. This study aimed to explore risk factors of early postoperative obstruction and to construct a nomogram to predict the possibility of occurrence.Methods: The records of 1437 patients who underwent elective colorectal surgery in Peking University People's Hospital from 2015 to 2020 were retrospectively collected. Risk factors of early postoperative bowel obstruction were identified by logistic regression analysis and a nomogram was then constructed. Bootstrap was applied to verify the stability of the model.Results: COPD, hypothyroidism, probiotic indications, duration of antibiotics, and time to postoperative feeding were identified as independent risk factors and were put into a nomogram for predicting early postoperative bowel obstruction. The nomogram showed robust discrimination, with the area under the receiver operating characteristic curve was 0.894 and was well-calibrated.Conclusion: A nomogram including independent risk factors of COPD, hypothyroidism, probiotic indications, duration of antibiotics, and time to postoperative feeding were established to predict the risk of early postoperative bowel obstruction. [ABSTRACT FROM AUTHOR]

Lysine acetylated modification was indicated to impact colorectal cancer (CRC)’s distant metastasis. However, the global acetylated proteins in CRC and the differential expressed acetylated proteins and acetylated sites between CRC primary and distant metastatic tumor remains unclear. Our aim was to construct a complete atlas of acetylome in CRC and paired liver metastases. Combining high affinity enrichment of acetylated peptides with high sensitive mass spectrometry, we identified 603 acetylation sites from 316 proteins, among which 462 acetylation sites corresponding to 243 proteins were quantified. We further classified them into groups according to cell component, molecular function and biological process and analyzed the metabolic pathways, domain structures and protein interaction networks. Finally, we evaluated the differentially expressed lysine acetylation sites and revealed that 31 acetylated sites of 22 proteins were downregulated in CRC liver metastases compared to that in primary CRC while 40 acetylated sites of 32 proteins were upregulated, of which HIST2H3AK19Ac and H2BLK121Ac were the acetylated histones most changed, while TPM2 K152Ac and ADH1B K331Ac were the acetylated non-histones most altered. These results provide an expanded understanding of acetylome in CRC and its distant metastasis, and might prove applicable in the molecular targeted therapy of metastatic CRC. Biological significance This study described provides, for the first time, that full-scale profiling of lysine acetylated proteins were identified and quantified in colorectal cancer (CRC) and paired liver metastases. The novelty of the study is that we constructed a complete atlas of acetylome in CRC and paired liver metastases. Moreover, we analyzed these differentially expressed acetylated proteins in cell component, molecular function and biological process. In addition, metabolic pathways, domain structures and protein interaction networks of acetylated proteins were also investigated. Our approaches shows that of the differentially expressed proteins, HIST2H3AK19Ac and H2BLK121Ac were the acetylated histones most changed, while TPM2 K152Ac and ADH1B K331Ac were the acetylated non-histones most altered. Our findings provide an expanded understanding of acetylome in CRC and its distant metastasis, and might prove applicable in the molecular targeted therapy of metastatic CRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is believed to progress through the adenoma-carcinoma sequence. The adenoma-carcinoma transition is an important window for early detection and intervention of CRC. In the present study, plasma samples from patients with CRC ( n = 120), patients with adenomatous polyps (AP) ( n = 120), and healthy controls ( n = 120) were collected. Plasma phospholipid levels were analyzed with liquid chromatography-tandem mass spectrometry. It was found that the plasma levels of major lysophosphatidylcholine (LPC) species were gradationally decreased from healthy controls, AP to CRC subjects. A formula including total saturated LPCs, 18:2 LPC and sphingosylphosphorylcholine (SPC) yielded a sensitivity and specificity of 88.3 and 80 % for separating CRC from healthy controls. An optimized model with total saturated LPCs, 20:4 LPC and sphingomyelins (SM) as markers yielded a sensitivity and specificity of 89 and 80 % for separating AP from the healthy controls. Moreover, with SM, SPC and saturated LPCs as markers, a model was made to separate CRC from AP with the sensitivity and specificity of 90 and 92.5 %, respectively. These data indicate that the plasma choline-containing phospholipid levels represent potential biomarkers to distinguish between healthy controls, AP and CRC cases, implying their clinical usage in CRC and/or AP-CRC progression detection. [ABSTRACT FROM AUTHOR]

We previously showed that B cell receptor associated protein 31(BAP31) was significantly upregulated in colorectal cancer compared with normal mucosa epithelia. However, its expression pattern and pathological role in colorectal cancer are not clearly understood. In this study, we investigated whether the expression of BAP31 was associated with the clinicopathological parameters of colorectal cancer. The expression pattern of BAP31 was detected by immunohistochemistry on a tissue microarray in both primary tumor and paired distant normal mucosa samples from 120 consecutive colorectal cancer patients. Furthermore, BAP31 protein expression was also determined in twenty colorectal adenomas and eight liver metastasis samples. There was positive expression of BAP31 in 64.17% of primary tumors and 6.67% in distant normal mucosa ( P=0.000). Negative expression of BAP31 was correlated with distant metastasis ( P=0.036) and lower tumor differentiation grade ( P=0.001). Patients with BAP31-negative expression showed significantly lower overall survival rate ( P=0.003) compared to patients with BAP31-positive expression. Our results demonstrate that BAP31 may serve as a candidate prognostic marker in colorectal cancer and negative BAP31 expression may lead to more aggressive invasion of colorectal cancer. [ABSTRACT FROM AUTHOR]

Objective: To investigate the capability of a radiomics model, which was designed to identify histopathologic growth pattern (HGP) of colorectal liver metastases (CRLMs) based on contrast-enhanced multidetector computed tomography (ceMDCT), to predict early response and 1-year progression free survival (PFS) in patients treated with bevacizumab-containing chemotherapy.Methods: Patients with unresectable CRLMs who were treated with bevacizumab-containing chemotherapy were included in this multicenter retrospective study. For each target lesion, the radiomics-diagnosed HGP (RAD_HGP) of desmoplastic (D) pattern or replacement (R) pattern was determined. Logistic regression and receiver operating characteristic (ROC) curves were used to assess lesion- and patient-based responses according to morphologic response criteria. One-year PFS was calculated using Kaplan-Meier curves. Hazard ratios for 1-year PFS were obtained through Cox proportional hazard regression analysis.Results: Among 119 study patients, 206 D pattern and 140 R pattern lesions were identified. In patients with multiple lesions, 52 had D pattern, 31 had R pattern, and 36 had mixed (D + R) pattern. The area under the curve value for RAD_HGP in predicting early response was 0.707 for lesion-based analysis and 0.720 for patient-based analysis. Patients with D pattern had a significantly longer PFS than patients with R pattern or mixed pattern (P < 0.001). RAD_HGP was the only independent predictor of 1-year PFS.Conclusions: HGP diagnosed using a radiomics model could be used as an effective predictor of PFS for patients with CRLMs treated with bevacizumab-containing chemotherapy. [ABSTRACT FROM AUTHOR]

• The expression of TDO2 in colorectal cancer is higher than that in normal tissues. • Invasion and migration of colorectal cancer cells may be affected by the TDO2. • TDO2 may be an indicator of poor prognosis of colorectal cancer. • The expression of Kyn pathway enzymes may have a potential relationship with increased AhR activity. The aim of this study was to explore the expression levels and biological significance of TDO2 in colorectal cancer (CRC). First, we explored the potential oncogenic roles of TDO2 across 33 tumors based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Second, we evaluated TDO2 protein expression in 55 CRC tissue samples and 30 cDNA samples by immunohistochemistry and qPCR. Third, we investigated the effect of TDO2 on CRC cells by cell proliferation, wound healing, invasion, and colony formation assays. Finally, we determined the protein that is most closely associated with TDO2 via bioinformatics analysis, enriched the key pathways, and verified them. The expression level of TDO2 was found to be associated with the tumor clinical stage in CRC. A high expression of TDO2 was associated with a poor outcome in CRC patients. Inhibition of TDO2 expression by RNAi in LoVo and HCT116 cell lines significantly reduced the proliferation, migration, and invasion abilities as well as colony formation abilities of cells. Further, knockdown of TDO2 expression induced inactivation of the TDO2–KYNU–AhR signaling pathway. The results suggest that TDO2 plays an important role in the progression of CRC. Accordingly, TDO2 is a potential therapeutic target in CRC. [ABSTRACT FROM AUTHOR]