• Molecules and Cells
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• v.42 no.11
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• pp.755-762
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• 2019

Despite decades of research into colorectal cancer (CRC), there is an ongoing need for treatments that are more effective and safer than those currently available. Lactic acid bacteria (LAB) show beneficial effects in the context of several diseases, including CRC, and are generally regarded as safe. Here, we isolated a Lactobacillus rhamnosus (LR)-derived therapeutic protein, p8, which suppressed CRC proliferation. We found that p8 translocated specifically to the cytosol of DLD-1 cells. Moreover, p8 down-regulated expression of Cyclin B1 and Cdk1, both of which are required for cell cycle progression. We confirmed that p8 exerted strong anti-proliferative activity in a mouse CRC xenograft model. Intraperitoneal injection of recombinant p8 (r-p8) led to a significant reduction (up to 59%) in tumor mass when compared with controls. In recent years, bacterial drug delivery systems (DDSs) have proven to be effective therapeutic agents for acute colitis. Therefore, we aimed to use such systems, particularly LAB, to generate the valuable therapeutic proteins to treat CRC. To this end, we developed a gene expression cassette capable of inducing secretion of large amounts of p8 protein from Pediococcus pentosaceus SL4 (PP). We then confirmed that this protein (PP-p8) exerted anti-proliferative activity in a mouse CRC xenograft model. Oral administration of PP-p8 DDS led to a marked reduction in tumor mass (up to 64%) compared with controls. The PP-p8 DDS using LAB described herein has advantages over other therapeutics; these advantages include improved safety (the protein is a probiotic), cost-free purification, and specific targeting of CRC cells.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3085-3088
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• 2016

Background: Worldwide, colorectal cancer (CRC) is reported to be the fourth most common cancer in men and the third most common in women. KRAS is a proto-oncogene located on the short arm of chromosome 12. The aim of this study was to evaluate the KRAS oncogene and its relationship it with clinicopathologic features in 33 Kurdish patients. Materials and Methods: Metastatic CRC between 2012 and 2016 that came to Imam Reza hospital, Kermanshah province, Iran, were analysed for KRAS mutations using allele specific PCR primers and pyrosequencing. Correlations between variables was analyzed in PASW SPSS and overall survival curves were plotted in Graph Pad prism 5. Results: The mean age for them at diagnosis was $51.5{\pm}12.6$ years (range, 22-76 years). Among the 33 patients that were sequenced, 12 samples in the KRAS gene had a nucleotide change, 11 in codon 12 and 1 in codon 13.There was no significant relationship between the mutation and clinical and pathological aspects of the disease. Conclusions: Knowledge of the KRAS status can help in decision-making to treat metastatic colorectal cancer patients more efficiently and increase survival. However, many Kurdish people due to economic problems are not able to do this valuable genetic test. In addition, we need more careful research of KRAS oncogene at the molecular level in young populations with more patients.

• Genomics & Informatics
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• v.17 no.4
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• pp.42.1-42.6
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• 2019

Robust identification of genetic alterations is important for the diagnosis and subsequent treatment of tumors. Screening for genetic alterations using tumor tissue samples may lead to biased interpretations because of the heterogeneous nature of the tumor mass. Liquid biopsy has been suggested as an attractive tool for the non-invasive follow-up of cancer treatment outcomes. In this study, we aimed to verify whether the mutations identified in primary tumor tissue samples could be consistently detected in plasma cell-free DNA (cfDNA) by digital polymerase chain reaction (dPCR). We first examined the genetic alteration profiles of three colorectal cancer (CRC) tissue samples by targeted next-generation sequencing (NGS) and identified 11 non-silent amino acid changes across six cancer-related genes (APC, KRAS, TP53, TERT, ARIDIA, and BRCA1). All three samples had KRAS mutations (G12V, G12C, and G13D), which were well-known driver events. Therefore, we examined the KRAS mutations by dPCR. When we examined the three KRAS mutations by dPCR using tumor tissue samples, all of them were consistently detected and the variant allele frequencies (VAFs) of the mutations were almost identical between targeted NGS and dPCR. When we examined the KRAS mutations using the plasma cfDNA of the three CRC patients by dPCR, all three mutations were consistently identified. However, the VAFs were lower (range, 0.166% to 2.638%) than those obtained using the CRC tissue samples. In conclusion, we confirmed that the KRAS mutations identified from CRC tumor tissue samples were consistently detected in the plasma cfDNA of the three CRC patients by dPCR.

• Clinical Endoscopy
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• v.55 no.6
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• pp.726-735
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• 2022

Inflammatory bowel disease (IBD) has a global presence with rapidly increasing incidence and prevalence. Patients with IBD including those with ulcerative colitis and Crohn's disease have a higher risk of developing colorectal cancer (CRC) compared to the general population. Risk factors for CRC in patients with IBD include long disease duration, extensive colitis, primary sclerosing cholangitis, family history of CRC, stricture, and prior dysplasia. Surveillance colonoscopy for CRC in patients with IBD should be tailored to individualized risk factors and requires careful monitoring every year to every five years. The current surveillance techniques are based on several guidelines. Chromoendoscopy with targeted biopsy is being recommended increasingly, and high-definition colonoscopy is gradually replacing standard-definition colonoscopy. However, it remains unclear whether chromoendoscopy, virtual chromoendoscopy, or white-light endoscopy has better efficiency when a high-definition scope is used. With the development of new endoscopic instruments and techniques, the paradigm of surveillance strategy has gradually changed. In this review, we discuss cutting-edge surveillance colonoscopy in patients with IBD including a review of literature.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6253-6255
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• 2014

Background: Colorectal cancer (CRC) is considered to be a main cause of malignancy-related death in the world, being commonly diagnosed in both men and women. It is the third leading cause of cancer dependent death in the world and there are one million new cases diagnosed per year. In Iran the incidence of colorectal cancer has increased during the last 25 years and it is the fifth cause of cancer in men and the third in women. Materials and Methods: In this article we analyzed the survival of 475 colorectal patients of Taleghani hospital in Tehran with the semi-parametric competing-risks model. Results: There were 55% male cases and at the time of the diagnosis most of the patients were between 48 and 67years old. The probability of a patient death from colorectal cancer with survival of more than 25 years was about 0.4. Body mass index, height, tumour site and gender had no influence. Conclusions: According to these data and by using semi-parametric competing-risks method, we found out that only age at diagnosis has a significant effect on these patient survival time.

• Development and Reproduction
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• v.20 no.1
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• pp.1-10
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• 2016

Molecular targeting for the altered signaling pathways has been proven to be effective for the treatment of many types of human cancer, including colorectal cancer (CRC). The dual phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 has shown to exhibit potent antitumor activity against solid tumors. Autophagy is a cellular lysosomal catabolic process to maintain metabolic homeostasis, which has been known to be induced in response to many therapeutic agents in cancer cells. This process is negatively regulated by mTOR and often acts as prosurvival or prodeath mechanism following cancer therapeutics. The current study was designed to investigate the antiproliferation activity of BEZ235 and to evaluate the role of autophagy induced by BEZ235 using HCT15 CRC cells bearing ras oncogene mutation. We found that BEZ235 decreases cell viability, which was mostly dependent on $G_1$ arrest of cell cycle via suppression of cyclin A expression. BEZ235 affects PI3K/Akt/mTOR signaling pathway by increasing the phosphorylation of AKT at $Ser^{473}$ and RAS/RAF/MEK/ERK pathway by decreasing the phosphorylation of ERK at $Tyr^{204}$. BEZ235 also stimulated autophagy induction as evidenced by the increased expression of LC3-II and abundant acidic vesicular organelles (AVOs) in the cytoplasm. In addition, the combination of BEZ235 with autophagy inhibitor chloroquine, a known antagonist of autophagy, counteracted the antiproliferation effect of BEZ235. Thus, our study indicates that autophagy induced in response to BEZ235 treatment appears to act as cell death mechanism in HCT15 CRC cells.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.2
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• pp.597-601
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• 2016

Background: Components of the systemic inflammatory response, combined to form inflammation-based prognostic scores (mGPS, NLR, PLR, PI, PNI) have been associated with overall survival. The aim of the present study was to compare various prognostic factors including many previously established parameters and such systemic inflammation-based prognostic scores in a series of incurable stage IV colorectal cancer (CRC) patients. Materials and Methods: Patients (n=167) with stage IV CRC undergoing surgical procedures between 2005 and 2013 were enrolled. Preoperatively (7-30 days before surgery), routine laboratory examinations were performed on the same day. We calculated scores using these data and analyzed the association with cancer specific survival (CSS) statistically. Results: Univariate analysis revealed significant associations between CSS and WBC, albumin, CRP, CEA values, mGPS, PNI, and PI values among preoperative factors. On multivariate analysis, high mGPS and high CEA independently predicted shorter CSS (p=0.001 and p=0.018). A new scoring system was constructed using mGPS and CEA. When patients were separated into three categorized using this system, the new score accurately predicted CSS (p < 0.001). Conclusions: The present study indicates that a new scoring system, consisting of mGPS and CEA, is a simple and useful tool in predicting the survival of patients with incurable stage IV CRC, and should be included in the routine assessment of these patients for decision making of appropriate treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.20
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• pp.9015-9019
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• 2014

The study aimed to compare the 2 main types of insurance used by colorectal cancer (CRC) patients in a university hospital in Thailand: universal coverage (UC) and 'Civil Servant Medical Benefit Scheme' (CSMBS) in terms of hospital expenditure and survival outcomes. CRC cases in stages I-IV who were operated on and had completed their adjuvant therapy in Songklanagarind Hospital from 2004 through 2013 were retrospectively reviewed regarding their hospital expenditure, focusing on surgical and chemotherapy costs. Of 1,013 cases analyzed, 524 (51.7%) were in the UC group while 489 (48.3%) belonged to the CSMBS group. Cases with stage IV disease were significantly more frequent in the UC group. Average total treatment expenditure (TTE) was 143,780 Thai Baht (THB) (1 US$ =~ 30 THB). The TTE increased with tumor stage and the chemotherapy cost contributed the most to the TTE increment. TTE in the CSMBS group was significantly higher than in the UC group for stage II-III CRCs. The majority of cases in the UC group (65.5%) used deGramont or Mayo as their first line regimen, and the proportion of cases who started with a capecitabine-based regimen (XELOX or $Xeloda^{(R)}$) was significantly higher in the CSMBS group (61.0% compared to 24.5% in the UC group, p-value < 0.01). On survival analysis, overall survival (OS) and progress free survival in the CSMBS group were significantly better than in the UC group. The 5-year OS in the CSMBS and UC groups were 84.3% and 74.6%, respectively (p-value < 0.01). In conclusion, the study indicates that in Thailand, the type of insurance influences resource utilization, especially the choice of chemotherapy, in CRC cases. This disparity in treatment, in turn, results in a gap in treatment outcomes.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.3
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• pp.927-930
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• 2012

Background and Objectives: Artificial neural networks (ANNs) are flexible and nonlinear models which can be used by clinical oncologists in medical research as decision making tools. This study aimed to predict distant metastasis (DM) of colorectal cancer (CRC) patients using an ANN model. Methods: The data of this study were gathered from 1219 registered CRC patients at the Research Center for Gastroenterology and Liver Disease of Shahid Beheshti University of Medical Sciences, Tehran, Iran (January 2002 and October 2007). For prediction of DM in CRC patients, neural network (NN) and logistic regression (LR) models were used. Then, the concordance index (C index) and the area under receiver operating characteristic curve (AUROC) were used for comparison of neural network and logistic regression models. Data analysis was performed with R 2.14.1 software. Results: The C indices of ANN and LR models for colon cancer data were calculated to be 0.812 and 0.779, respectively. Based on testing dataset, the AUROC for ANN and LR models were 0.82 and 0.77, respectively. This means that the accuracy of ANN prediction was better than for LR prediction. Conclusion: The ANN model is a suitable method for predicting DM and in that case is suggested as a good classifier that usefulness to treatment goals.

• Molecules and Cells
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• v.41 no.5
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• pp.423-435
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• 2018

This investigation was aimed at working out the combined role of lncRNA H19, miR-29b and Wnt signaling in the development of colorectal cancer (CRC). In the aggregate, 185 CRC tissues and corresponding para-carcinoma tissues were gathered. The human CRC cell lines (i.e. HT29, HCT116, SW480 and SW620) and normal colorectal mucosa cell line (NCM460) were also purchased. Si-H19, si-NC, miR-29b-3p mimics, miR-29b-3p inhibitor, si-PGRN and negative control (NC) were, respectively, transfected into the CRC cells. Luciferase reporter plasmids were prepared to evaluate the transduction activity of $Wnt/{\beta}-catenin$ signaling pathway, and dual-luciferase reporter gene assay was arranged to confirm the targeted relationship between H19 and miR-29b-3p, as well as between miR-29b-3p and PGRN. Finally, the proliferative and invasive capacities of CRC cells were appraised through transwell, MTT and scratch assays. As a result, overexpressed H19 and down-expressed miR-29b-3p displayed close associations with the CRC patients' poor prognosis (P < 0.05). Besides, transfection with si-H19, miR-29b-3p mimic or si-PGRN were correlated with elevated E-cadherin expression, decreased snail and vimentin expressions, as well as less-motivated cell proliferation and cell metastasis (P < 0.05). Moreover, H19 was verified to directly target miR-29b-3p based on the luciferase reporter gene assay (P < 0.05), and miR-29b-3p also bound to PGRN in a direct manner (P < 0.05). Finally, addition of LiCl ($Wnt/{\beta}-catenin$ pathway activator) or XAV93920 ($Wnt/{\beta}-catenin$ pathway inhibitor) would cause remarkably altered E-cadherin, c-Myc, vimentin and snail expressions, as well as significantly changed transcriptional activity of ${\beta}-catenin/Tcf$ reporter plasmid (P < 0.05). In conclusion, the lncRNA H19/miR-29b-3p/PGRN/Wnt axis counted a great deal for seeking appropriate diagnostic biomarkers and treatment targets for CRC.