Pathogenesis Of Colorectal Carcinoma Research Articles

Laterality influence on gene expression of DNA damage repair in colorectal cancer

Colorectal carcinoma (CRC) is the third most common malignancy worldwide, and second in number of deaths in the world. The molecular pathogenesis of CRC is heterogeneous and can affect several genes. Moreover, genomic instability is recognized as an important part of CRC carcinogenesis and is tightly connected to DNA damage response. DNA damage repair (DDR) pathways are intrinsically associated with cancer development and establishment. Traditionally, CRC is considered as one coherent disease, however, new evidence shows that left and right-sided CRC present differences observed in clinical settings, as well as in pre-clinical studies. Therefore, this study aimed to investigate the impact of DDR transcriptional profiles on survival in different sublocations of the colon and rectum using Cox regression, survival analysis and differential gene expression. Right side colon (RSC) has DDR genes’ expression associated only with higher risk of death, while left side colon (LSC) and Rectum have most genes’ expression associated with lower risk. The pattern is the same with survival analysis. All significant DDR genes had lower expression associated with better survival in RSC, as opposed to LSC and Rectum. Our results demonstrate that RSC is distinctively different from LSC and Rectum. LSC and Rectum have similar DDR expression profiles.

Exploring the pathogenesis of colorectal carcinoma complicated with hepatocellular carcinoma via microarray data analysis.

Background: Despite the increasing number of research endeavors dedicated to investigating the relationship between colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC), the underlying pathogenic mechanism remains largely elusive. The aim of this study is to shed light on the molecular mechanism involved in the development of this comorbidity. Methods: The gene expression profiles of CRC (GSE90627) and HCC (GSE45267) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of psoriasis and atherosclerosis, three kinds of analyses were performed, namely, functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification, survival analysis and co-expression analysis. Results: A total of 150 common downregulated differentially expressed genes and 148 upregulated differentially expressed genes were selected for subsequent analyses. The significance of chemokines and cytokines in the pathogenesis of these two ailments is underscored by functional analysis. Seven gene modules that were closely connected were identified. Moreover, the lipopolysaccharide-mediated signaling pathway is intricately linked to the development of both diseases. Finally, 10 important hub genes were identified using cytoHubba, including CDK1, KIF11, CDC20, CCNA2, TOP2A, CCNB1, NUSAP1, BUB1B, ASPM, and MAD2L1. Conclusion: Our study reveals the common pathogenesis of colorectal carcinoma and hepatocellular carcinoma. These common pathways and hub genes may provide new ideas for further mechanism research.

Pathways Related to Colon Inflammation Are Associated with Colorectal Carcinoma: A Transcriptome- and Methylome-Wide Study.

The association of chronic inflammation with colorectal carcinoma (CRC) development is well known in ulcerative colitis (UC). However, the role of inflammatory changes in sporadic CRC pathogenesis is less widely appreciated. In this study, in the first step using RNA-seq, we identified gene-pathway-level changes in UC-associated CRC (UC CRC, n = 10) and used the changes as a proxy for inflammation in human colon to ask if there were associations of inflammatory pathway dysregulations in sporadic CRC pathogenesis (n = 8). We found down-regulations of several inflammation-related metabolic pathways (nitrogen metabolism, sulfur metabolism) and other pathways (bile secretion, fatty acid degradation) in sporadic CRC. Non-inflammation-related changes included up-regulation of the proteasome pathway. In the next step, from a larger number of paired samples from sporadic CRC patients (n = 71) from a geographically and ethnically different population and using a different platform (microarray), we asked if the inflammation-CRC association could be replicated. The associations were significant even after stratification by sex, tumor stage, grade, MSI status, and KRAS mutation status. Our findings have important implications to widen our understanding of inflammatory pathogenesis of sporadic CRC. Furthermore, targeting of several of these dysregulated pathways could provide the basis for improved therapies for CRC.

Abstract 4038: Discovery of potent and selective inhibitors of the protein tyrosine phosphatases PTPN2 and PTPN1 to trigger anti-tumor immunity through sensitization of tumor cells and activation of immune cells

Abstract Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) has emerged as a promising cancer immunotherapy target. Previously, we reported on the functional role of PTPN2 in the pathogenesis of colorectal carcinoma (CRC). We demonstrated increased PTPN2 phosphatase activity correlates with disease progression and decreased immune responses in tumor tissues, while loss of PTPN2 in T-cells or in dendritic cells (DCs) reduces tumor burden in several CRC models and potentiates anti-PD1 efficacy (Katkeviciute et al., 2021). Others reported that loss of PTPN2 in tumor cells sensitizes to immune-mediated tumor killing (Manguso et al., 2017; Goh et al., 2022). Thus, PTPN2 was proposed as a critical node to modulate anti-tumor immunity, and PTPN2 inhibition is expected to enhance anti-tumor immunity by sensitizing tumor cells and by activating immune cells. Recently, also the closely related phosphatase PTPN1 (PTP1B) was demonstrated to restrain T-cell mediated tumor killing (Wiede et al., 2022). Inhibition of Protein Tyrosine Phosphatases has historically been a demanding area for drug discovery. However, both allosteric PTP inhibitors (eg targeting SHP2/PTPN11) and catalytic-site inhibitors (targeting PTPN2/N1) have recently progressed to clinical studies. We now identified a chemical series of novel dual PTPN2/N1 inhibitors. These inhibitors bind to the catalytic site of PTPN2, as confirmed by crystallography. The best molecules of the series are low nM inhibitors of PTPN2 and PTPN1 enzymes with excellent selectivity across other phosphatases. As an immediate consequence of PTPN2/N1 inhibition, these compounds augment phosphorylation of STAT1 and/or STAT5 isoforms in myeloid and T-cell lines, and in primary T-cells, macrophages and DCs. This results in immune-cell activation as evidenced by increased production of effector cytokines (e.g. IFNγ), immune-activation, levels of cytotoxicity markers in T-cells (e.g. granzyme B) as well as upregulation of antigen presentation and co-stimulatory markers in macrophages and DCs. Furthermore, inhibition of PTPN2/N1 sensitizes murine and human cancer cell lines to IFNγ, and enhances immune-mediated tumor killing in co-culture assays in vitro. In vivo evaluation of selected examples is in progress and results will be presented at the conference. Our data indicate that inhibition of PTPN2/N1 phosphatase activity is a powerful pharmacologic strategy to promote anti-tumor immunity, with strong potential to be exploited for cancer immunotherapy both as a single agent treatment in anti-PD1 refractory cancers, and in combination with anti-PD1 therapy. Citation Format: Kalliopi Pervolaraki, Egle Katkeviciute, Dominique Lambin, Sandro Boland, Amuri Kilonda, Vincent Pericolle, Marnik Nijs, Wanda Haeck, Kristine Metzger, Hugo Klaassen, Arnaud Marchand, Patrick Chaltin, Matthias Versele, Marianne Spalinger, Michael Scharl. Discovery of potent and selective inhibitors of the protein tyrosine phosphatases PTPN2 and PTPN1 to trigger anti-tumor immunity through sensitization of tumor cells and activation of immune cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4038.

Oxidative imbalance increases the risk for colonic polyp and colorectal cancer development.

The role of oxidative stress in the pathogenesis of colorectal carcinoma (CRC) has garnered considerable interest recently. Specific oxidative factors have been implicated in the pathogenesis of adenomatous polyps and ultimately adenocarcinoma. To evaluate the effect of oxidative imbalance as quantified by specific serological markers in the development of sporadic colon adenocarcinoma. A total of 170 patients that underwent endoscopy of the lower gastrointestinal tract in a tertiary center within 3 years were included in the study. They were allocated in three groups; those with sporadic colon adenocarcinoma (n = 56, 32.9%), those with colonic polyps (n = 33, 19.4%) and healthy controls (n = 81, 47.7%). All patients were evaluated for oxidant activity and antioxidant capacity with serum measurements of specific markers such as vitamins A, 25(OH) D3, E, C, B12, folic acid, glutathione, selenium (Se), zinc (Zn), free iron (Fe2+), and malondialdehyde and results were compared between groups. Serum levels of vitamins C, E, D, Se, Zn, vitamin B12 and total antioxidant capacity were significantly lower in the combined neoplasia/polyp group than in the control group (P = 0.002, P = 0.009, P < 0.001, P < 0.001, P < 0.001, P = 0.020 and P < 0.001, correspondingly). Increased levels of vitamin E (P = 0.004), vitamin D (P < 0.001), Se (P < 0.001) and Zn (P < 0.001) seem to bestow a protective effect on the development of CRC. For vitamin D (P < 0.001) and Zn (P = 0.036), this effect seems to extend to the development of colon polyps as well. On the other hand, elevated serum levels of malondialdehyde are associated with a higher risk of CRC (OR = 2.09 compared to controls, P = 0.004). Regarding colonic polyp development, increased concentrations of vitamin Α and Fe2+ are associated with a higher risk, whereas lower levels of malondialdehyde with a lower risk. Increased oxidative stress may play an important role in the pathogenesis and progression of CRC. Antioxidants' presence may exert a protective effect in the very early stages of colon carcinogenesis.

Implications of estrogen and its receptors in colorectal carcinoma.

Estrogens have been implicated in the pathogenesis of various cancer types, including colorectal carcinoma (CRC). Estrogen receptors such as ERα and ERβ activate intracellular signaling cascades followed by binding to estrogen, resulting in important changes in cellular behaviors. The nuclear estrogen receptors, i.e. ERβ and ERα are responsible for the genomic actions of estrogens, whereas the other receptor, such as G protein-coupled estrogen receptor (GPER) regulates rapid non-genomic actions, which lead to secondary gene expression changes in cells. ERβ, the predominant estrogen receptor expressed in both normal and non-malignant colonic epithelium, has protective roles in colon carcinogenesis. ERβ may exert the anti-tumor effect through selective activation of pro-apoptotic signaling, increasing DNA repair, inhibiting expression of oncogenes, regulating cell cycle progression, and also by changing the micro-RNA pool and DNA-methylation. Thus, a better understanding of the underlying mechanisms of estrogen and its receptors in CRC pathogenesis could provide a new horizon for effective therapeutic development. Furthermore, using synthetic or natural compounds as ER agonists may induce estrogen-mediated anti-cancer activities against colon cancer. In this study, we report the most recent pre-clinical and experimental evidences related to ERs in CRC development. Also, we reviewed the actions of naturally occurring and synthetic compounds, which have a protective role against CRC development by acting as ER agonist.

Role of TP53 Gene Mutations in the Pathogenesis of Colorectal Carcinoma

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the world. The underlying molecular mechanisms that drive colorectal carcinogenesis are not fully known. However, P53 gene mutation, the most reported somatic mutation, is observed in about 50% of colorectal cancer patients.&#x0D; Colorectal carcinoma is multifactorial. TP53 gene, the most novel tumor suppressor gene, acts as a major gatekeeper by preserving the genetic composition of a cell and prevents the oncogenic transformation of a cell. MDM2 and CUL-4A belong to the E3 ubiquitin ligase family, blocks P53 activation, and thus act as an oncogene. TRIM67 also has defective ligase activity, and its mutation is seen in about 80% of colorectal carcinomas. miRNA inhibits the tumor suppressor effect of TP53 and downstream signaling pathways, resulting in carcinogenesis. K RAS, WT1, IGF-1 are other markers of colorectal carcinoma. P53 antibodies produce by colorectal carcinomatous tissue are the markers used for screening and diagnosis.&#x0D; P53 mutation drives a phenomenon of colorectal tumorigenesis. It serves as a biomarker, a prognostic factor, and a therapeutic target of colorectal carcinoma. Further studies are strongly recommended to improve the therapeutic approach of colorectal carcinoma.

Hsa_circ_0005100 regulates tumorigenicity of colorectal carcinoma via miR-145-5p/MACC1 axis.

BackgroundCircular RNAs (circRNAs) are a kind of RNA molecules involved in the regulation of cancer progression, including colorectal carcinoma (CRC); nevertheless, their regulation mode is blurry. In the present work, we attempted to reveal the characteristics of hsa_hsa_circ_0005100 in CRC.MethodsDifferential expressions of hsa_circ_0005100, FMN2 mRNA, microRNA‐145‐5p (miR‐145‐5p), and MACC1 were indicated by qRT‐PCR and Western blot. The capacities of cell growth and motility were validated by the MTT assay, flow cytometry assay, EdU assay, colony formation assay, and transwell assay. Moreover, the targeted relationship of miR‐145‐5p and hsa_circ_0005100 or MACC1 was distinguished by dual‐luciferase reporter assay. The animal experiment was implemented to confirm the influence of hsa_circ_0005100 on tumorigenesis in vivo.ResultsHsa_circ_0005100 and MACC1 expression levels were increased, but miR‐145‐5p expression level was diminished in CRC. Hsa_circ_0005100 knockdown repressed cell proliferation, cell cycle, migration, and invasion, while expedited cell apoptosis in CRC cells. Furthermore, miR‐145‐5p was disclosed to block CRC via overturning MACC1. Hsa_circ_0005100 targeted miR‐145‐5p to modulate MACC1. Additionally, hsa_circ_0005100 knockdown also attenuated tumorigenesis in vivo.ConclusionHsa_circ_0005100 was a vital regulator in the development of CRC by miR‐145‐5p/MACC1 axis, which deepened the understanding of CRC pathogenesis from circRNA insights.

A Systematic Review and Meta-analysis on the Occurrence of Biomarker Mutation in Colorectal Cancer among the Asian Population.

Globally, colorectal carcinoma (CRC) is the third most common cancer and the third major cause of cancer-related death in both sexes. KRAS and BRAF mutations are almost mutually exclusively involved in the pathogenesis of CRC. Both are major culprits in treatment failure and poor prognosis for CRC. Method. A systematic review and meta-analysis of various research was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. This trial is registered with PROSPERO CRD42021256452. The initial search included 646 articles; after the removal of noneligible studies, a total of 88 studies was finally selected. Data analysis was carried out using OpenMeta Analyst and Comprehensive Meta-Analysis 3.0 (CMA 3.0) software to investigate the prevalence of KRAS and BRAF mutations among patients with CRC in Asia. Results. The meta-analysis comprises of 25,525 sample sizes from Asia with most being male 15,743/25525 (61.7%). Overall prevalence of KRAS mutations was (59/88) 36.3% (95% CI: 34.5-38.2) with I2 = 85.54% (P value < 0.001). In 43/59 studies, frequency of KRAS mutations was majorly in codon 12 (76.6% (95% CI: 74.2–78.0)) and less in codon 13 (21.0% (95% CI: 19.1-23.0)). Overall prevalence of BRAF mutations was 5.6% (95% CI: 3.9-8.0) with I2 = 94.00% (P value < 0.001). When stratified according to location, a higher prevalence was observed in Indonesia (71.8%) while Pakistan has the lowest (13.5%). Conclusion. Total prevalence of KRAS and BRAF mutations in CRC was 36.6% and 5.6%, respectively, and the results conformed with several published studies on KRAS and BRAF mutations.

Heme oxygenase-1 & 2 and their potential contribution in heme induced colorectal carcinogenesis

BackgroundLiterature suggests Heme oxygenase (HO) system to be a double-edged sword which can promote both cytoprotection as well as carcinogenicity. The aim of this study was to investigate the role of heme in HO-1 and HO-2 induced colorectal carcinogenesis and the clinicopathological significance of their expressions in patients with colorectal carcinoma (CRC). MethodsHO-1 and HO-2 expression alterations in normal colonic epithelial (FHC) and colon cancer cells (SW480) were explored following treatment with 0 µM, 25 µM, 100 µM and 250 µM concentrations of hemin, using qPCR. Fifty paired CRC and adjacent non-neoplastic samples were subjected to qPCR to determine the HO-1 and HO-2 expression. Clinicopathological associations of HO-1 and HO-2 expression levels were determined. ResultsLow concentrations of hemin caused upregulation and high concentration caused downregulation of HO-1 expression, whereas HO-2 expression was significantly downregulated with all hemin concentrations in FHC. HO-1 expression in SW480 was increased with all hemin concentrations and HO-2 expression was downregulated at the highest hemin concentration. HO-1 and HO-2 expressions in adjacent non-neoplastic tissue was significantly higher than that of CRC. Expression of HO-1 was significantly higher than HO-2, in both CRC and adjacent non-neoplastic tissue. Sex, HFE expression and lymph-vascular invasion were significantly correlated with HO-1 expression. HO-2 expression showed significant associations with staging, local spread and recurrence of tumour. ConclusionHO-1 and HO-2 expression is respectively induced and repressed by exogenous hemin in normal colon and colon cancer cells. HO-1 and HO-2 expression profiles in CRC are correlated with the assessed clinicopathological features of CRC, suggesting the possible implications of HO expression status in CRC pathogenesis.

Chosen Antioxidant Enzymes GPx4 and GPx8 in Human Colorectal Carcinoma: Study of the Slovak Population.

Background and Objectives: Nowadays colorectal carcinoma (CRC) is one of the most common causes of death in patients with malignant neoplasms worldwide. Our work aimed to determine the possible involvement of glutathione peroxidases 4 and 8 (GPx4 and GPx8) in this specific tumor process. Materials and Methods: The expression of GPx4 and GPx8 in 58 specimens of human colorectal cancer tissues and normal tissues was detected by the indirect immunohistochemical method under a light microscope. Statistical analysis was done by Chi-squared test. Histological findings were compared with data such as gender, age, tumor grade, histotype and lymph nodes alteration. Results: In all specimens of healthy tissue the presence of both, GPx4 and GPx8, was detected in the cytoplasm of epithelial cells. On the other hand, a positive immunohistochemical reaction against GPx4 only in 41.4% and against GPx8 only in 29.3% of human colorectal adenocarcinoma specimens were observed. Any significant difference between the presence of GPx and the age, the gender of the patient, tumor grade, histotype of cancer and the lesion of regional lymph nodes has not been detected. Conclusions: Our foundation could mean, that GPx4 and GPx8 have no important role in CRC pathogenesis, but the loss of these enzymes probably indicates a serious pathological process ongoing in the large intestine. To our knowledge, this is the first paper describing GPx8 presence in human colorectal carcinoma.

SPINK1 contributes to proliferation and clonal formation of HT29 cells through Beclin1 associated enhanced autophagy.

We aimed to explore the molecular mechanism that were involved in SPINK1-induced proliferation and clonogenic survival of human colorectal carcinoma (CRC) HT29 cells. Initially, we generated HT29 cells either permanently silencing or overexpressing SPINK1 protein. The results showed that SPINK1 overexpression (OE) significantly stimulated the proliferation and clonal formation of HT29 cells at the varied time points. Secondly, we found SPINK1 OE enhanced the ratio of LC3II/LC3I and the level of autophagy-related gene 5 (ATG5), whereas SPINK1 knockdown (Kd) reversed the above outcome under normal culturing and/or fasting condition in the cells, indicating its role in autophagy enhancement. Moreover, LC3-GFP-transfected SPINK1-OE HT29 cells strengthened the fluorescence intensity compared with the untransfected control. Chloroquine (CQ) significantly decreased the level of autophagy in both control and SPINK1-OE HT29 cells. The autophagy inhibitors, CQ and 3-Methyladenine (3-MA), remarkably inhibited the proliferation and colony formation of SPINK1-OE HT29 cells, while ATG5 upregulation resulted in the growth of the cells, suggesting the important function of autophagy in cell's growth. Thirdly, SPINK1-induced autophagy was independently of mTOR signaling as p-RPS6 and p-4EBP1 were activated in SPINK1-OE HT29 cells. Instead, Beclin1 up and down regulation were clearly observed in SPINK1-OE and SPINK1 Kd HT29 cells, respectively. Moreover, Beclin1 silencing apparently reduced autophagy in SPINK1-OE HT29 cells, indicating that SPINK1-induced autophagy was closely associated with Beclin1. Collectively, SPINK1-promoted proliferation and clonal formation of HT29 cells were closely associated with Beclin1 associated enhanced autophagy. The above findings would open a new window for probing the role of SPINK1-related autophagic signaling in the pathogenesis of CRC.

Colonic polyps in Nigerians, a change in trends: A retrospective single-center clinicopathological study

Background: Adenomatous polyps in the colon are recognized precursors of colorectal carcinoma; however, the low incidence of these polyps in sub-Saharan Africans has led many to believe that the pathway of colorectal cancer may differ in this region. The objective of this study was aimed to determine the change in trends of colonic polyps in Nigeria. Methods: This was a 10-year retrospective review of all colonic polyp specimens received at the Department of Pathology in our hospital utilizing the histopathology request cards and hematoxylin and eosin-stained slides. The data were analyzed using the IBM SPSS Statistics (version 23; IBM Corporation, Armonk, New York, USA). Results: A total of 131 cases were reviewed. The age of patients ranged from 5 to 86 years with a mean age of 55 years. The male-to-female ratio was 1.6:1. The mean age was 59.4 years. Of the 131 cases reviewed, 62 patients had adenomatous polyps, 49 had inflammatory polyps while 20 others included juvenile polyps, hyperplastic polyps, and hamartomatous polyps. Conclusion: Adenomatous polyps are increasingly being seen among Africans in the sub-Sahara region and perhaps they are not as rare as it was once thought provided the facilities for the diagnosis are available. They may yet play a more important role than has been ascribed to them in the pathogenesis of colorectal carcinomas in Africans.

The role of appendectomy and cholecystectomy in the pathogenesis of colorectal carcinomas

BackgroundSeveral alterations in the gastrointestinal tract which occur after appendectomy or cholecystectomy have been suggested to raise the risk of developing colorectal carcinoma. Given the frequency that these procedures are performed, we sought to determine whether a history of either cholecystectomy or appendectomy increased the risk of future colorectal carcinoma. MethodsWe determined the number of patients with a history of appendectomy and cholecystectomy who developed colorectal carcinoma between January 2018 and February 2021, as well as the latency time between the two diseases. Secondly, we carried out a data-collection spanning 15 years after the primary surgery (January 2005–December 2006). ResultsThe post-cholecystectomy state is significantly more frequently observed in patients treated for colorectal carcinomas (both male and female), especially among those who developed right-sided or left-sided colon cancer, as opposed to anorectal cancer (p = 0.53). However, the time elapsed between the two diseases is 20–25 years, which appears to be markedly long regarding such a multifactorial disease as the colorectal carcinoma. No similar extra risk was observed among patients having appendectomy. Secondly, we found no extra risk during the first 15 years after cholecystectomy. ConclusionAlthough a statistically higher risk of colon cancer is observed after the removal of the gallbladder, but the latency time is long. Thus, cholecystectomy may not be an independent risk factor for colorectal carcinogenesis. Altogether, the patient is not exposed to a higher risk of colorectal carcinogenesis after having cholecystectomy.

Ins and Outs of Heat Shock Proteins in Colorectal Carcinoma: Its Role in Carcinogenesis and Therapeutic Perspectives.

Cancer cells can reprogram their metabolic activities and undergo uncontrolled proliferation by utilizing the power of heat shock proteins (HSPs). HSPs are highly conserved chaperones that facilitate the folding of intracellular proteins under stress. Constitutively, HSPs are expressed at low levels, but their expression upregulates in response to a wide variety of insults, including anticancer drugs, allowing cancer cells to develop chemoresistance. In recent years, several researchers have reported that HSPs could be an important therapeutic target in difficult-to-treat cancers such as colorectal carcinoma (CRC). Worldwide, CRC is the second most common type of cancer and the second leading cause of cancer-related deaths. The molecular complexity of CRC and the coexisting inflammatory conditions present a significant obstacle to developing effective treatment. Recently, considerable progress has been made in enhancing our understanding of the role of HSPs in CRC pathogenesis. Moreover, novel therapeutic strategies targeting HSPs, either alone or in combination with other anticancer agents, have been reported. Herein, we present an overview of the functional mechanisms and the diagnostic and prognostic potential of HSPs in CRC. We also discuss emerging anti-CRC strategies based on targeting HSPs.

PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair.

Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.

Interaction between Microsatellite Instability (MSI) and Tumor DNA Methylation in the Pathogenesis of Colorectal Carcinoma.

Simple SummaryIn colorectal cancer (CRC), mutations may occur in short, repeated DNA sequences, known as microsatellite instability (MSI). Tumor DNA methylation is another molecular change now recognized as an important biomarker in CRC. In a genome-wide scale, for the first time, we explored whether DNA methylation is associated with MSI status in CRC. We analyzed 250 paired samples (tumor and corresponding normal) from 125 CRC patients (m = 72, f = 53) at different stages. We found that many genes were methylated in tumor tissue compared to normal tissue. However, almost four times more genes showed such methylation changes in the tumor if the patient who also had MSI compared to patients without MSI. Our study shows an association of MSI and DNA methylation in CRC. The study also indicates an opportunity for potential use of certain immune checkpoint inhibitors (CTLA4 and HAVCR2 inhibitors) in CRC with MSI.In colorectal cancer (CRC), the role of microsatellite instability (MSI) is well known. In a genome-wide scale, for the first time, we explored whether differential methylation is associated with MSI. We analyzed 250 paired samples from 125 CRC patients (m = 72, f = 53) at different stages. Of them, 101 had left-sided CRC, 30 had MSI, 34 had somatic mutation in KRAS proto-oncogene (KRAS), and 6 had B-Raf proto-oncogene (BRAF) exon 15p.V600E mutation. MSI was more frequent in right-sided tumors (54% vs. 17%, p = 0.003). Among the microsatellite stable (MSS) CRC, a paired comparison revealed 1641 differentially methylated loci (DML) covering 686 genes at FDR 0.001 with delta beta ≥ 20%. Similar analysis in MSI revealed 6209 DML covering 2316 genes. ANOVA model including interaction (Tumor*MSI) revealed 23,322 loci, where the delta beta was different among MSI and MSS patients. Our study shows an association between MSI and tumor DNA methylation in the pathogenesis of CRC. Given the interaction seen in this study, it may be worth considering the MSI status while looking for methylation markers in CRC. The study also indicates an opportunity for potential use of certain immune checkpoint inhibitors (CTLA4 and HAVCR2 inhibitors) in CRC with MSI.

CD163+ macrophages suppress T cell response by producing TGF-β in pediatric colorectal polyps

The local immune response plays an important role in the pathogenesis of colorectal carcinoma. Patients with colorectal polyps are at increased risk of colorectal cancer. However, the immunoregulation of early-stage colorectal polyps remain unknown. In the study, 202 biopsy samples from 80 pediatric patients with colorectal polyps and from 42 normal controls were collected. We found that the number of CD4+, CD8+T cells and CD19+B cells were reduced, whereas CD68+macrophages (Mϕ) were increased in colorectal polyps compared to the distal normal tissue from the same patients and the tissue from healthy donors. The frequency of Mϕwas negatively correlated with the number of CD4+ and CD8+T cells but not CD19+B cells in colorectal polyps. We further identified that CD163 was highly expressed on Mϕϕ from colorectal polyps compared to those from normal controls. Furthermore, real-time PCR revealed that TGF-β, but not IL-10 and IL-4, was increased in colorectal polyps. Immunofluorescence and flow cytometry showed that TGF-β was predominantly produced by CD163+Mϕ. In vitro experiments demonstrated that the supernatant from cultured polyps induced CD163 expression and TGF-β production in blood-derived Mϕ. A co-culture experiment revealed that purified Mϕ from colorectal polyps suppressed T cell proliferation. Based on these results, we hypothesized that abundant CD163+Mϕ may promote the progression of colorectal polyps by inhibiting the local T cell response through TGF-β production.

APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production.

APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production.

Hypermethylation of heparanase 2 promotes colorectal cancer proliferation and is associated with poor prognosis

BackgroundThe epigenetic abnormality of tumor-associated genes contributes to the pathogenesis of colorectal carcinoma (CRC). However, methylation in colorectal cancer is still poorly characterized.MethodBy integration of DNA methylation data from the GEO database and gene expression data from The Cancer Genome Atlas database, the aberrantly methylated genes involved in CRC tumorigenesis were identified. Subsequent in vitro experiments further validated their role in CRC.ResultsWe performed integrative genomic analysis and identified HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. K-M survival analysis showed that hypermethylation–low expression of heparanase 2 (HPSE2) was related to poor patient prognosis. Overexpression of HPSE2 reduced cell proliferation in vivo and in vitro. HPSE2 could regulate the p53 signaling pathway to block the cell cycle in G1 phase.ConclusionHPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. HPSE2 performs a tumor suppressive function by activating the p53/ p21 signaling cascade. The promoter hypermethylation of HPSE2 is a potential therapeutic target in patients with CRC, especially those with late-stage CRC.