Progression Of Colorectal Adenoma Research Articles

Gut microbiota and serum metabolite signatures along the colorectal adenoma-carcinoma sequence: Implications for early detection and intervention

AimOur study focuses on the microbial and metabolomic profile changes during the adenoma stage, as adenomas can be considered potential precursors to colorectal cancer through the adenoma-carcinoma sequence. Identifying possible intervention targets at this stage may aid in preventing the progression of colorectal adenoma (CRA) to malignant lesions. Furthermore, we evaluate the efficacy of combined microbial and metabolite biomarkers in detecting CRA. MethodsFecal metagenomic and serum metabolomic analyses were performed for the discovery of alterations of gut microbiome and metabolites in CRA patients (n = 26), Colorectal cancer (CRC) patients (n = 19), Familial Adenomatous Polyposis (FAP) patients (n = 10), and healthy controls (n = 20). Finally, analyzing the associations between gut microbes and metabolites was performed by a Receiver Operating Characteristic (ROC) curve. ResultsOur analysis present that CRA patients differ significantly in gut microflora and serum metabolites compared with healthy controls, especially for Lachnospiraceae and Parasutterella. Its main metabolite, butyric acid, concentrations were raised in CRA patients compared with the healthy controls, indicating its role as a promoter of colorectal tumorigenesis. α-Linolenic acid and lysophosphatidylcholine represented the other healthy metabolite for CRA. Combining five microbial and five metabolite biomarkers, we differentiated CRA from CRC with an Area Under the Curve (AUC) of 0.85 out of this performance vastly superior to the specificity recorded by traditional markers CEA and CA199 in such differentiation of these conditions. ConclusionsThe study underlines significant microbial and metabolic alterations in CRA with a novel insight into screening and early intervention of its tumorigenesis.

Associations of circulating leptin levels with colorectal adenoma and colorectal cancer: a case-control and Mendelian randomization study

To explore the causal association between circulating leptin levels and the risk of colorectal adenoma and colorectal cancer. We collected demographic and clinical data and serum samples from 497 patients with colorectal adenoma, 955 patients with colorectal cancer, and 911 healthy individuals from the First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Cancer Hospital, Zhuji People's Hospital, and Lin'an District First People's Hospital. Instrumental variables of leptin were selected and genotyping tests were performed. A logistic regression model and stratified analysis were used to evaluate the association of serum leptin levels with colorectal adenoma, colorectal cancer, and the progression of colorectal adenoma to colorectal cancer. Genetic risk score (GRS) and single nucleotide polymorphisms (SNPs) were further used as instrumental variables in one-sample and two-sample Mendelian randomization analyses leveraging two-stage least squares and inverse-variance weighted methods to estimate the causal association of leptin levels with the risk of colorectal adenoma, colorectal cancer, and progression of colorectal adenoma to colorectal cancer. High levels of leptin, compared with its lowest quartile, were positively correlated with colorectal adenoma (P=0.005) and negatively with colorectal cancer (P < 0.001) and the risk of progression of colorectal adenoma to colorectal cancer (P < 0.001). Mendelian randomization analysis showed that GRS of leptin, either weighted or not, was not significantly correlated with the risk of colorectal adenoma, colorectal cancer, or the progression of colorectal adenoma to colorectal cancer, nor did the two-sample Mendelian randomization study support an association between leptin and the risk of colorectal cancer (P>0.05). Although the case-control study suggests probable correlations of leptin with the risk of colorectal adenoma, colorectal cancer, and colorectal adenoma progression to colorectal cancer, Mendelian randomization studies did not support a causal association of leptin with the risks of colorectal adenoma, colorectal cancer, or colorectal adenoma progression to colorectal cancer.

Colonoscopy Combined with Me-Nbi to Observe the Canceration Characteristics of Colon Polyps and the Correlation of RHOC Protein Expression.

The current study was carried out to analyze the characteristics of colon polyps canceration observed by colonoscopy combined with ME-NBI (Magnifying Endoscopy combined with Narrow-Band Imaging) and its correlation with RhoC (Ras homolog gene family, member C) protein expression. For this purpose, A total of 300 patients with colorectal polyps and cancerous lesions (192 colorectal polyps and 200 cancerous lesions) who were treated in the digestive endoscopy room of the hospital and underwent colonoscopy were selected, and they were divided into polyp group and malignant lesion according to the diagnosis results. groups, 150 cases in each group. There were 75 patients with non-adenomatous polyps and 75 patients with adenomatous polyps in the polyp group; 75 patients with high-grade neoplasia and cancerous changes in the malignant group. The microvascular structure and surface structure of the lesions were observed by colonoscopy, and the correlation between microvascular morphological characteristics and RhoC protein expression was analyzed. Results showed that the probability of positive RhoC protein expression in the polyp group was significantly lower than that in the malignant transformation group, and the difference was statistically significant (P<0.05). In the malignant transformation group, the positive rate of RhoC expression in mucosal and submucosal superficial infiltration of 150 patients with colon polyp carcinoma was lower than that in submucosal deep infiltration, and the difference was statistically significant (P<0.05). NICE (National Institute for Clinical Excellence) type 2 was diagnosed as colorectal superficial submucosal The sensitivity, specificity, and accuracy of colorectal submucosal invasion were 73.1%, 84.6%, and 83.2%, respectively; the sensitivity, specificity, and accuracy of NICE type 3 in diagnosing colorectal submucosal invasion were 74.6%, 96.8%, and 92.7%, respectively. . Type 2 and type 3 lesions with cancerous features in NICE classification were correlated with the expression of RhoC protein (P<0.05). In conclusion, NICE classification under colonoscopy combined with magnifying colonoscopy has a good effect on colorectal lesions. Differential diagnostic value, RhoC protein is highly expressed in colon cancer and is closely related to the occurrence of colon cancer and the depth of lesion invasion. With the progression of colorectal adenomas, the expression of RhoC protein in the lesions gradually increased.

Molecular characterization of colorectal adenoma and colorectal cancer via integrated genomic transcriptomic analysis.

Colorectal adenoma can develop into colorectal cancer. Determining the risk of tumorigenesis in colorectal adenoma would be critical for avoiding the development of colorectal cancer; however, genomic features that could help predict the risk of tumorigenesis remain uncertain. In this work, DNA and RNA parallel capture sequencing data covering 519 genes from colorectal adenoma and colorectal cancer samples were collected. The somatic mutation profiles were obtained from DNA sequencing data, and the expression profiles were obtained from RNA sequencing data. Despite some similarities between the adenoma samples and the cancer samples, different mutation frequencies, co-occurrences, and mutually exclusive patterns were detected in the mutation profiles of patients with colorectal adenoma and colorectal cancer. Differentially expressed genes were also detected between the two patient groups using RNA sequencing. Finally, two random forest classification models were built, one based on mutation profiles and one based on expression profiles. The models distinguished adenoma and cancer samples with accuracy levels of 81.48% and 100.00%, respectively, showing the potential of the 519-gene panel for monitoring adenoma patients in clinical practice. This study revealed molecular characteristics and correlations between colorectal adenoma and colorectal cancer, and it demonstrated that the 519-gene panel may be used for early monitoring of the progression of colorectal adenoma to cancer.

UTP18-mediated p21 mRNA instability drives adenoma-carcinoma progression in colorectal cancer

Colorectal cancer (CRC) often develops slowly from adenoma, but the underlying mechanism remains unclear, hampering the prevention or treatment of colorectal adenoma-carcinoma progression. In this study, we use in-depth quantitative proteomics combined with survival analysis, revealing that the ribosome protein U3 small nucleolar RNA-associated protein 18 homolog (UTP18) is consistently upregulated in the progression of colorectal adenoma to carcinoma and is associated with adenoma recurrence, effective serodiagnosis, and poor prognosis of CRC. Furthermore, deSUMOylation induces the nucleocytoplasmic transport of UTP18, driving cell-cycle progression and tumorigenesis via mediation of the instability of p21 mRNA. In addition, the growth and ribosome biogenesis of adenoma organoids is found to be promoted by overexpression of UTP18. Thus, UTP18 contributes to multiple roles in adenogenesis and malignancy of CRC, suggesting that it could be a potential biomarker and drug target for colorectal adenoma and cancer.

Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.

Low expression of the dynamic network markers FOS/JUN in pre-deteriorated epithelial cells is associated with the progression of colorectal adenoma to carcinoma

BackgroundDeterioration of normal intestinal epithelial cells is crucial for colorectal tumorigenesis. However, the process of epithelial cell deterioration and molecular networks that contribute to this process remain unclear.MethodsSingle-cell data and clinical information were downloaded from the Gene Expression Omnibus (GEO) database. We used the recently proposed dynamic network biomarker (DNB) method to identify the critical stage of epithelial cell deterioration. Data analysis and visualization were performed using R and Cytoscape software. In addition, Single-Cell rEgulatory Network Inference and Clustering (SCENIC) analysis was used to identify potential transcription factors, and CellChat analysis was conducted to evaluate possible interactions among cell populations. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analysis (GSVA) analyses were also performed.ResultsThe trajectory of epithelial cell deterioration in adenoma to carcinoma progression was delineated, and the subpopulation of pre-deteriorated epithelial cells during colorectal cancer (CRC) initialization was identified at the single-cell level. Additionally, FOS/JUN were identified as biomarkers for pre-deteriorated epithelial cell subpopulations in CRC. Notably, FOS/JUN triggered low expression of P53-regulated downstream pro-apoptotic genes and high expression of anti-apoptotic genes through suppression of P53 expression, which in turn inhibited P53-induced apoptosis. Furthermore, malignant epithelial cells contributed to the progression of pre-deteriorated epithelial cells through the GDF signaling pathway.ConclusionsWe demonstrated the trajectory of epithelial cell deterioration and used DNB to characterize pre-deteriorated epithelial cells at the single-cell level. The expression of DNB-neighboring genes and cellular communication were triggered by DNB genes, which may be involved in epithelial cell deterioration. The DNB genes FOS/JUN provide new insights into early intervention in CRC.

Identification and clinical validation of key genes as the potential biomarkers in colorectal adenoma

BackgroundColorectal cancer (CRC), ranking third in cancer prevalence and second in mortality worldwide, is mainly derived from colorectal adenoma (CRA). CRA is a common benign disease in the intestine with rapidly increasing incidence and malignant potential. Therefore, this study aimed to recognize significant biomarkers and original pathogenesis in CRA.MethodsTranscriptome data of GSE8671, GSE37364, and GSE15960 were downloaded from the Gene Expression Omnibus (GEO) datasets, and differentially expressed genes (DEGs) were screened. Functional pathways enrichment, protein–protein interaction (PPI) network, stem-correlation analysis, CIBERSORT, risk score and survival analyses were performed. RT-qPCR and immunohistochemical staining were applied to verify our results. ResultsScreening for significant DEGs in each dataset, we identified 230 robust DEGs, including 127 upregulated and 103 downregulated genes. Functional pathways enrichment showed that these DEGs were distinctly enriched in various tumor-associated pathways, such as growth factor activity, extracellular structure organization, neutrophil activation, and inflammatory response. We filtered out two hub genes via STRING and Modules analysis, including CA2 and HSD11B2. Stem-correlation analysis displayed that hub genes were negatively associated with stem-related genes (Olfm4, CD44, CCND1 and MYC). The CIBERSORT algorithm indicated that Macrophage2, activated mast cells, and Neutrophils promoted CRA progression through inflammation. Survival analysis showed that CA2 and HSD11B2 were positively associated with survival outcomes in CRC.ConclusionOur study has successfully identified the critical role of two core genes in the development and oncogenesis of CRA, which provides novel insight into the underlying pathogenesis, potential biomarkers and therapeutic targets.

Research Progress of Intestinal Microecology in the Pathogenesis of Colorectal Adenoma and Carcinogenesis.

Colorectal adenoma is a precancerous lesion that may progress to colorectal cancer. Patients with colorectal adenoma had a 4-fold higher risk of developing colorectal malignancy than the rest of the population, with approximately 80% of colorectal cancer originating from colorectal adenoma. Therefore, preventing the occurrence and progression of colorectal adenoma is crucial in reducing the risk for colorectal cancer. The human intestinal microecology is a complex system consisting of numerous microbial communities with a sophisticated structure. Interactions among intestinal microorganisms play crucial roles in maintaining normal intestinal structure, digestion, absorption, metabolism, and other functions. The colorectal system is the largest microbial bank or fermentation system in the human body. Studies suggest that intestinal microecological imbalance, one of the most important environmental factors, may play an essential role in the occurrence and development of colorectal adenoma and colorectal cancer. Based on the complexity of studying the gut microbiota ecosystem, its specific role in the occurrence and development of colorectal adenoma is yet to be elucidated. In addition, further studies are expected to provide new insights regarding the prevention and treatment of colorectal adenoma. This article reviews the relationship and mechanism of the diversity of the gut microbiota, the relevant inflammatory response, immune regulation, and metabolic changes in the presence of colorectal adenomas.

Enrichment of Prevotella intermedia in human colorectal cancer and its additive effects with Fusobacterium nucleatum on the malignant transformation of colorectal adenomas

BackgroundOwing to the heterogeneity of microbiota among individuals and populations, only Fusobacterium nucleatum and Bacteroides fragilis have been reported to be enriched in colorectal cancer (CRC) in multiple studies. Thus, the discovery of additional bacteria contributing to CRC development in various populations can be expected. We aimed to identify bacteria associated with the progression of colorectal adenoma to carcinoma and determine the contribution of these bacteria to malignant transformation in patients of Han Chinese origin.MethodsMicrobiota composition was determined through 16S rRNA V3–V4 amplicon sequencing of autologous adenocarcinomas, adenomatous polyps, and non-neoplastic colon tissue samples (referred to as “tri-part samples”) in patients with CRC. Enriched taxa in adenocarcinoma tissues were identified through pairwise comparison. The abundance of candidate bacteria was quantified through genomic quantitative polymerase chain reaction (qPCR) in tissue samples from 116 patients. Associations of candidate bacteria with clinicopathological features and genomic and genetic alterations were evaluated through odds ratio tests. Additionally, the effects of candidate bacteria on CRC cell proliferation, migration, and invasion were evaluated through the co-culture of CRC cells with bacterial cells or with conditioned media from bacteria.ResultsPrevotella intermedia was overrepresented in adenocarcinomas compared with paired adenomatous polyps. Furthermore, co-abundance of P. intermedia and F. nucleatum was observed in tumor tissues. More notably, the coexistence of these two bacteria in adenocarcinomas was associated with lymph node involvement and distant metastasis. These two bacteria also exerted additive effects on the enhancement of the migration and invasion abilities of CRC cells. Finally, conditioned media from P. intermedia promoted the migration and invasion of CRC cells.ConclusionThis report is the first to demonstrate that P. intermedia is enriched in colorectal adenocarcinoma tissues and enhances the migration and invasion abilities of CRC cells. Moreover, P. intermedia and F. nucleatum exert additive effects on the malignant transformation of colorectal adenomas into carcinomas. These findings can be used to identify patients at a high risk of malignant transformation of colorectal adenomas or metastasis of CRC, and they can accordingly be provided optimal clinical management.

Two ST11 Klebsiella pneumoniae strains exacerbate colorectal tumorigenesis in a colitis-associated mouse model

ABSTRACT Sequence type (ST) 11 is one of the major lineages of carbapenem-resistant Klebsiella pneumoniae (CRKP). Although the gastrointestinal (GI) carriage of CRKP predisposes individuals to subsequent infections, little is known for its impact on gut homeostasis. In this study, we investigated the association between ST11 CRKP colonization and colorectal cancer (CRC). Two ST11 CRKP, KPC160111 (KL47) and KPC160132 (KL64), were selected as the representative strains. We used azoxymethane (AOM) and dextran sodium sulfate (DSS) to initiate a colitis-associated CRC model. Both strains established prolonged colonization in the GI tract of the AOM-DSS-treated BALB/c mice and aggravated gut dysbiosis. Under this AOM-DSS-induced setting, ST11 K. pneumoniae colonization significantly promoted the growth and progression of colorectal adenomas to high-grade dysplasia. Numerous crypts were formed inside the enlarged adenomas, in which CD163+ tumor-associated macrophages accumulated. Similarly, ST11 K. pneumoniae also increased the population size of the CD163+ macrophages with the M2 phenotype in the peritoneal cavity of LPS-primed BALB/c mice. When applied to RAW264.7 cells, ST11 K. pneumoniae polarized the macrophages toward an M2 phenotype through the inhibition of IKK-NFκB and the activation of STAT6-KLF4-IL-10. Through the M2-skewing ability, ST11 K. pneumoniae promoted the accumulation of CD163+ macrophages in the adenomatous crypts to create an immunosuppressive niche, which not only accommodated the extended stay for its own sake but also deteriorated colorectal tumorigenesis.

Abstract 1804: Role of microRNAs in colorectal adenoma progression

Abstract Colorectal cancer (CRC) survival rates are stage related and majority of patients (75%) with CRC have sporadic of the disease which is in form of adenoma. Most of colorectal adenocarcinomas precursors are adenomatous polyps. Moreover, CRC appears to be an age related disease and studies have shown that mutations in mtDNA appear to accumulate with age because of inadequate repair. Also, oxidative stress has been shown to affect mitochondrial proteins resulting in a decrease of mitochondrial function associated with the precursor lesions of cancer. Recent findings suggest that the mitochondrion has sequences that code for certain miRNA which can regulate different pathways frequently dysregulated in cancer including colorectal cancer (CRC). Isolation of mitochondria RNA from colorectal precancerous polyps, cancer, and normal adjacent tissue samples was performed and assessed for gene expression differences using quantitative reverse transcription PCR. We demonstrate that mitochondria genome expression of miRNAs miR-24, miR 181, miR 210, and miR 21 in colorectal tissue samples varies during disease progression. Expression of microRNAs 24, 181, and 210 progressively increased from the earliest precancerous polyp to cancer. In addition, miR-210 and miR-181 expression increased 3 folds in villous adenomas when compared to tubular adenoma. Meanwhile, miR 21 increased progressively in adenoma tissues but decreased almost 4 folds in cancer tissues when compared to villous adenoma tissue. These results suggest miRNAs within the mitochondria genome may regulate important mitochondrial functional pathways leading to a more favorable environment for transformation or progression of adenomas to cancerous tumors. Citation Format: LaShanale M. Wallace, Aneese F. Chaudhry, Karen I. Aikhionbare, Xuebiao Yao, Felix O. Aikhionbare. Role of microRNAs in colorectal adenoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1804.

Abstract 4638: Colorectal adenoma-to-carcinoma progression: The role of miR-17-92 cluster

Abstract Background Chromosomal instability plays an important role in the progression of colorectal adenoma to carcinoma. We previously observed that specific non-random DNA copy number changes (8q, 13q, 20q gain, and 8p, 15q, 17p, 18q loss) were already present in the benign adenoma component of malignant polyps (i.e. adenomas with a focus of cancer). This indicates that these specific DNA copy number changes are associated with the progression from adenoma to cancer. DNA copy number dosage affects the expression of different loci, which may play an important functional role in the colorectal adenoma-to-carcinoma progression. We observed that overexpression of the miR-17-92 cluster (located on 13q) is associated with gain of 13q, one of the cancer associated DNA copy number changes. The aim of the present study was to investigate the biological meaning of miR-17-92 overexpression in benign adenomas and its role in adenoma-to-carcinoma progression. Methods Patient-derived colorectal adenoma organoids were used as model system. Two different background adenoma organoids were transduced with a miR-17-92 expression vector. Overexpression of members of the miR-17-92 cluster in the transduced adenoma organoids was confirmed by real-time quantitative RT-PCR for all individual miRNAs. Both miR-17-92-overexpressing organoids and their counterparts containing empty vectors (controls) were subjected to mRNA sequencing and subsequent differential gene expression analysis and subsequent establishement of a miR-17-92 gene expression signature. Enrichment of the miR-17-92 gene signature was evaluated in an independent series of 52 colorectal adenoma and carcinoma tissue samples. In vitro proliferation rates as well as invasion capacity of the transduced organoids were evaluated by measuring the size of the organoids and by using transwell invasion assays, respectively. Results We successfully overexpressed the miR-17-92 cluster in the two adenoma-derived organoids. Expression of 42 genes was significantly different (FDR&amp;lt;0.05, &amp;gt;4 fold difference) between organoids transduced with the miR-17-92 cluster and those transduced with the empty vector. In addition, in the series of 52 tumor tissue samples this gene signature could separate adenomas from carcinomas and was enriched in tumours with 13q gain. In vitro functional assays showed that proliferation capacity did not change after overexpression of the miR17-92 cluster in adenoma organoids, but capacity to invade was acquired. Conclusion We confirmed that overexpression of the miR-17-92 cluster leads to downstream gene expression alterations associated with colorectal cancer. Moreover, we showed that overexpression of this miRNA cluster promotes invasion of adenoma organoids in vitro. These results support a role of this locus in the progression from adenoma to carcinoma. Citation Format: Sanne R. Martens-de Kemp, Malgorzata A. Komor, Rosa Hegi, Marianne Tijssen, Anne S. Bolijn, Gerrit A. Meijer, Connie R. Jimenez, Remond J. Fijneman, Beatriz Carvalho. Colorectal adenoma-to-carcinoma progression: The role of miR-17-92 cluster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4638.

Decreased Colorectal Adenoma Risk After Helicobacter pylori Eradication: A Retrospective Cohort Study.

Helicobacter pylori infection is associated with colorectal adenoma and confers a 1.3- to 2.26-fold increased risk. We evaluated the association between H. pylori and the progression of colorectal adenoma. This retrospective cohort study included 615 adults with no history of colorectal adenoma or cancer at baseline who participated in a repeated, regular health screening examination, which included a bidirectional gastrointestinal endoscopy, between July 2006 and June 2015. A gastric biopsy specimen from each subject was tested for H. pylori. During follow-up, the incidence rates of colorectal adenoma progression in participants with persistent H. pylori infections (persistent group) and those whose infections had previously been successfully eradicated (eradication group) were 160.52 and 51.60 per 1000 person-years, respectively (P = .0003). After adjustment for confounding factors, the persistent group exhibited a higher risk of colorectal adenoma than the eradication group (hazard ratio = 3.04, 95% CI 1.899, 5.864). The colorectal adenoma ratio of patients uninfected with H. pylori was similar to that of the eradication group (23.93% vs 20.12%, P = .328). Persistent H. pylori infection was associated significantly with the independent development of colorectal adenoma. H. pylori infection may have a pathophysiological role in colorectal adenoma development and, after successful eradication of H. pylori, the colorectal adenoma ratio might decrease.

The expression and significance of calcium channel activated protein 43 in colorectal adenoma and colorectal carcinoma

Objective To explore the expression of calcium channel activated protein 43 (Cap43) in normal colorectal mucosa, colorectal adenoma and colorectal carcinoma, and to analyze the relationships among different histological types of colorectal adenomas and colorectal carcinoma. Methods Immunohistochemistry was used to exzamine the location and expression of Cap43 in the colorectal tissues, colorectal carcinoma tissues and colorectal carcinoma tissues. Real-time fluorescent quantitative polymerase chain reaction (FQ-PCR) was used to detect Cap43 mRNA expression. Results The positive expression rate of Cap43 in normal colorectal mucosa, colorectal colorectal adenoma and and carcinoma tissues was 31.7%, 63.8% and 91.7% respectively, with significant differences among them (P=0.000). The positive expression rate of Cap43 in tubular adenoma, mixed pattern of adenoma, and villous adenoma was 52.5%, 60.0% and 90.0% respectively, also with significant differences among them (P=0.016). The Cap43 mRNA expression of the colorectal carcinoma, villous adenoma, the mixed pattern of adenoma, tubular adenoma, and normal colorectal mucosa was 19.552±6.338, 13.018±2.417, 7.323±2.131, 3.660±1.309, and 1.119±0.871 respectively (F=25.943, P=0.028). Conclusion Cap43 is correlated with canceration of colorectal adenoma and the development of colorectal carcinoma. Detecting the expression of Cap43 can evaluate the progression of colorectal adenoma and the development of colorectal carcinoma. Cap43 may be the molecular biological indicator for predicting canceration of colorectal adenoma. Key words: Colorectal adenoma; Colorectal carcinoma; Calcium channel activated protein 43

Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the ApcMin/+ mouse model of intestinal tumorigenesis

Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis that paracrine Cox-2-mediated signalling from macrophages drives adenoma growth and progression in vivo in the ApcMin/+ mouse model of intestinal tumorigenesis. Using a transgenic C57Bl/6 mouse model of Cox-2 over-expression driven by the chicken lysozyme locus (cLys-Cox-2), which directs integration site-independent, copy number-dependent transgene expression restricted to macrophages, we demonstrated that stromal macrophage Cox-2 in colorectal (but not small intestinal) adenomas from cLys-Cox-2 x ApcMin/+ mice was associated with significantly increased tumour size (P = 0.025) and multiplicity (P = 0.025), compared with control ApcMin/+ mice. Transgenic macrophage Cox-2 expression was associated with increased dysplasia, epithelial cell Cox-2 expression and submucosal tumour invasion, as well as increased nuclear β-catenin translocation in dysplastic epithelial cells. In vitro studies confirmed that paracrine macrophage Cox-2 signalling drives catenin-related transcription in intestinal epithelial cells. Paracrine macrophage Cox-2 activity drives growth and progression of ApcMin/+ mouse colonic adenomas, linked to increased epithelial cell β-catenin dysregulation. Stromal cell (macrophage) gene regulation and signalling represent valid targets for chemoprevention of colorectal cancer.

Difference in expression of two neurokinin-1 receptors in adenoma and carcinoma from patients that underwent radical surgery for colorectal carcinoma.

Mechanisms underlying tumor progression remain a main problem in the diagnosis and treatment of patients with tumors. The present study compared the expression of full-length neurokinin-1 receptors (fl-NK-1R) and truncated neurokinin-1 receptors (tr-NK-1R) in adenoma and carcinoma from patients with colorectal carcinoma, to explore their possible contributions in adenoma-carcinoma progression. Samples were collected immediately following colorectal carcinoma surgery. Using reverse transcription-quantitative polymerase chain reaction and immunohistochemical staining, the relative mRNA and protein levels of tr-NK-1R and fl-NK-1R were compared in adenoma and carcinoma. tr-NK-1R mRNA was significantly upregulated (1.7 fold; P=0.026) in carcinoma tissues compared with adenoma tissues, while the fl-NK-1R transcription level showed no difference (P=0.438). No significant change was observed in the fl-NK-1R protein level in adenoma, carcinoma and peri-carcinoma tissues (P=0.244). However, total neurokinin-1 receptor (NK-1R) protein levels in adenoma and carcinoma tissues were significantly increased compared to peri-carcinoma tissue (P=0.026 and P=0.007, respectively). The outcomes suggested that the increase in total NK-1R protein in adenoma and carcinoma tissues is the result of the increase in tr-NK-1R levels. The present findings indicate that tr-NK-1R serves an important role in colorectal adenoma progression, with a possible role in adenoma-carcinoma progression. Thus, tr-NK-1R may be used as a marker for diagnosing and treating patients with colorectal adenomas.

The expression and significance of Kiss1 protein in colon adenoma and colon carcinoma

Objective To investigate the expression and significance of Kiss1 protein in colon adenoma and colon carcinoma. Methods Immunohistochemistry and real-time fluorescent quantitative polymerase chain reaction (FQ-PCR) were used to detect the location and expression of Kiss1 in the 20 normal colon mucosae, 30 colon carcinomae, 80 colon adenomae. Results The positive expression rate of Kiss1 protein in normal colorectal mucosa, colorectal adenoma and colorectal carcinoma tissues was 93.3%, 58.8% and 5.0% respectively, with significant differences among them (P=0.005). The positive expression rate of Kiss1 protein in tubular adenoma, mixed pattern of adenoma and villous adenoma was 80.0%, 66.7% and 35.0% respectively, with significant differences among them (P=0.005). FQ-PCR showed that the Kiss1 mRNA expression rate was 28.85±8.34, 14.61±1.65, 7.58±1.31, 2.26±1.56 and 0.50±0.40 in normal colorectal mucosa, tubular adenoma, mixed pattern of adenoma, villous adenoma and colorectal carcinoma, respectively. Conclusion Kiss1 is correlated with canceration of colorectal adenoma and the development of colorectal carcinoma. Detecting the expression of Kiss1 can evaluate the progression of colorectal adenoma and the development of colorectal carcinoma. Key words: Colorectal adenoma; Colorectal carcinoma; Kiss1

The expression and clinical significance of connexin 32 in colorectal adenoma and colorectal carcinoma

Objective To explore the expression of connexin 32 in normal colorectal mucosa, colorectal adenomas and colorectal carcinoma, and to analyze its relationships with different histological types of colorectal adenomas and colorectal carcinoma. Methods Immunohistochemistry was used to exzamine the location and expression of connnexin 32 in the colorectal tissues, colorectal carcinoma tissues and colorectal carcinoma tissues. Real-time fluorescent quantitative polymerase chain reaction (FQ-PCR) was used to detect connexin 32 mRNA expression. Results There was a significant correlation between up-regulated expression of connexin 32 and unfavorable variables, including nodal metastasis, Dukes stage and differentiation degree (P=0.032). There was no obvious difference in age and sex (P=0.061). The positive expression rate of connexin 32 protein in normal colorectal mucosa, colorectal adenoma and colorectal carcinoma tissues was 66.7%, 36.2% and 5.0% respectively, with significant differences among them (P=0.000). The positive expression rate of connexin 32 protein in tubular adenoma, mixed pattern of adenoma and villous adenoma was 47.5%, 35.0% and 15.0% respectively, with significant differences among them (P=0.047). FQ-PCR showed that the expression of connexin 32 gradually decreased in normal colorectal mucosa, tubular adenoma, mixed pattern of adenoma, villous adenoma and colorectal carcinoma (P=0.006). Conclusion Connexin 32 is correlated with canceration of colorectal adenoma and the development of colorectal carcinoma. Detecting the expression of connexin 32 can evaluate the progression of colorectal adenoma and the development of colorectal carcinoma. Key words: Colorectal adenoma; Real-time fluorescent quantitative polymerase chain reaction; Connexin 32

The expression and significance of minichromosome maintenance protein 2 in colorectal adenoma and colorectal carcinoma

Objective To explore the expression of minichromosome maintenance protein 2 (MCM2) in normal colorectal mucosa, colorectal adenomas and colorectal carcinoma, and to analyze the relationships among different histological types of colorectal adenomas and colorectal carcinoma. Methods Immunohistochemistry was used to exzamine the location and expression of MCM2 in the colorectal tissues, colorectal adenoma tissues and colorectal carcinoma tissues. Real-time fluorescent quantitative polymerase chain reaction (FQ-PCR) was used to detect MCM2 mRNA and connexin-32 mRNA expression. Results (1) Immunohistochemistry: The positive expression rate of MCM2 protein in normal colorectal mucosa, colorectal adenoma and colorectal carcinoma tissues was 16.7%, 55.0% and 80.0% respectively, with significant differences among them (P=0.031). The positive expression rate of MCM2 in tubular adenoma, mixed pattern of adenoma and villous adenoma was 40.0%, 65.0% and 75.0% respectively, also with significant differences among them (P=0.022). (2) FQ-PCR: The MCM2 mRNA expression in the normal colorectal mucosa, tubular adenoma, the mixed pattern of adenoma, villous adenoma, and colorectal carcinoma was 1.187±0.923, 4.126±1.339, 9.577±0.838, 22.150±4.077 and 48.020±4.811, respectively. The expression of MCM2 gradually increased in colorectal carcinoma, villous adenoma, the mixed pattern of adenoma, tubular adenoma, and normal colorectal mucosa (F=55.512, P=0.029). SNK multiple comparisons displayed that the differences about any two groups of the total mean showed statistical significance. Conclusion MCM2 is correlated with canceration of colorectal adenoma and the development of colorectal carcinoma. Detecting the expression of MCM2 can evaluate the progression of colorectal adenoma and the development of colorectal carcinoma. They may be the molecular biological indicators for predicting canceration of colorectal adenoma. Key words: Colorectal adenoma; Colorectal carcinoma; Immunohistochemistry; Minichromosome maintenance protein 2