Pathways Of Carcinogenesis Research Articles

Genomic landscape of colorectal carcinogenesis.

The molecular pathogenesis of solid tumour was first assessed in colorectal cancer (CRC). To date, ≤ 100 genes with somatic alterations have been found to inter-connectively promote neoplastic transformation through specific pathways. The process of colorectal carcinogenesis via genome landscape is reviewed on the basis of an adenoma-to-carcinoma sequence, as shown by serial histological and epidemiological observations. The relevant literatures from PubMed (1980-2021) have been reviewed for this article. The major routes of CRC development, chromosomal instability (CIN), microsatellite instability (MSI), and the serrated route either via CIN or MSI, proceed through the respective molecular pathway of colorectal carcinogenesis. Particular aspects of CRC carcinogenesis can also be determined by evaluating familial CRCs (FCRC) and genotype-phenotype correlations. Specific causative gene alterations still leave to be identified in several FCRCs. Otherwise, recently verified FCRC can be particularly notable, for example, EPCAM-associated Lynch syndrome, polymerase proofreading-associated polyposis, RNF43-associated polyposis syndrome or NTHL1 tumour syndrome, and hereditary mixed polyposis syndrome. The oncogenic landscape is described, including representative pathway genes, the three routes of carcinogenesis, familial CRCs, genotype-phenotype correlations, the identification of causative genes, and consensus molecular subtypes (CMS). Whole genome research using multi-gene panels (MGPs) has facilitated high through-put detection of previously unidentified genes involved in colorectal carcinogenesis. New approaches designed to identify rare variants are recommended to consider their alterations implicated in the molecular pathogenesis.

Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis

Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis

Securin overexpression correlates with the activated Rb/E2F1 pathway and histone H3 epigenetic modifications in raw areca nut-induced carcinogenesis in mice

BackgroundRaw areca nut (RAN) consumption induces oral, esophageal and gastric cancers, which are significantly associated with the overexpression of pituitary tumor transforming gene 1/securin and chromosomal instability (CIN). An association of Securin/PTTG1 upregulation and gastric cancer in human was also demonstrated earlier. Since the molecular mechanism underlying securin upregulation remains unclear, this study intended to investigate the association of securin upregulation with the Rb-E2F1 circuit and epigenetic histone (H3) modification patterns both globally and in the promoter region of the securin gene.MethodsSix groups of mice were used, and in the treated group, each mouse consumed 1 mg of RAN extract with lime per day ad libitum in the drinking water for 60 days, after which the dose was increased by 1 mg every 60 days. Histopathological evaluation of stomach tissues was performed and securin expression was analysed by immunoblotting as well as by immunohistochemistry. ChIP-qPCR assays were performed to evaluate the recruitment of different histone modifications in the core promoter region of securin gene as well as its upstream and downstream regions.ResultsAll mice developed gastric cancer with securin overexpression after 300 days of feeding. Immunohistochemistry data revealed hyperphosphorylation of Rb and upregulation of E2F1 in the RAN-treated samples. Increased trimethylation of H3 lysine 4 and acetylation of H3 lysine 9 and 18 both globally and in the promoter region of the securin gene were observed by increasing the levels of lysine-N-methyltransferase 2A, lysine-acetyltransferase, EP-300 and PCAF after RAN treatment. ChIP-qPCR data revealed that the quantity of DNA fragments retrieved from the immunoprecipitated samples was maximum in the -83 to -192 region than further upstream and the downstream of the promoter for H3K4Me3, H3K9ac, H3K18ac and H3K9me3.ConclusionsRAN-mediated pRb-inactivation induced securin upregulation, a putative E2F1 target, by inducing misregulation in chromatin remodeling in its promoter region, which led to transcriptional activation and subsequent development of chromosomal instability. Therefore, present results have led to the hypothesis that RAN-induced changes in the epigenetic landscape, securin overexpression and subsequent elevation of chromosomal instability is probably byproducts of inactivation of the pRb pathway.

Новый эпигенетический путь канцерогенеза, ассоциированного с helicobacter pylori

Новый эпигенетический путь канцерогенеза Helicobacter pylori инициируется триггерами-онкогенами бактерии. Главный механизм канцерогенеза — тирозинкиназное фосфорилирование с избыточной активацией тирозинкиназ и активированием ЕRK MARK сигнальных путей нормальной пролиферации клетки, что нарушает нормальную пролиферацию и приводит к неконтролируемому росту клеток, трансформации и, как результат, к туморогенезу.

Identification of the critical genes and miRNAs in hepatocellular carcinoma by integrated bioinformatics analysis.

Hepatocellular carcinoma (HCC) is a global health problem with complex etiology and pathogenesis. Microarray data are increasingly being used as a novel and effective method for cancer pathogenesis analysis. An integrative analysis of genes and miRNA for HCC was conducted to unravel the potential prognosis of HCC. Two gene microarray datasets (GSE89377 and GSE101685) and two miRNA expression profiles (GSE112264 and GSE113740) were obtained from Gene Expression Omnibus database. A total of 177 differently expressed genes (DEGs) and 80 differently expressed miRNAs (DEMs) were screened out. Functional enrichment of DEGs was proceeded by Clue GO and these genes were significantly enriched in the chemical carcinogenesis pathway. A protein-protein interaction network was then established on the STRING platform, and ten hub genes (CDC20, TOP2A, ASPM, NCAPG, AURKA, CYP2E1, HMMR, PRC1, TYMS, and CYP4A11) were visualized via Cytoscape software. Then, a miRNA-target network was established to identify the hub dysregulated miRNA. A key miRNA (hsa-miR-124-3p) was filtered. Finally, the miRNA-target-transcription factor network was constructed for hsa-miR-124-3p. The network for hsa-miR-124-3p included two transcription factors (TFs) and five targets. These identified DEGs and DEMs, TFs, targets, and regulatory networks may help advance our understanding of the underlying pathogenesis of HCC.

A Decrease in CD44 on Cell Surfaces (MKN-45 cell line) After RELA Knockout Using CRISPR/Cas9.

The NF-kB signaling pathway was introduced as a key pathway in carcinogenesis that is induced by inflammation in gastrointestinal malignancies. The RelA transcription factor is an important component of this signaling pathway. Furthermore, CD44 is implicated in the tumorigenesis and metastasis of gastric cancer. The aim of this study was to assay the effect of RELA knockout on CD44 expression in MKN45 cells. CRISPR/Cas9 was used to knock out RELA in MKN-45. The medianfluorescence intensity (MFI) of CD44 before and after RELA knockout is analyzed in MKN45. The CRISPR/Cas9 vector pSpCas9 (BB)-2A-Puro (PX459) was used for gRNA cloning (two guides). The MKN-45 cell line was co-transfected. The purified co-transfected cells with puromycin were cultured and used for the RELA gene expression assay by real-time PCR. Flow cytometry was used for the analysis of the MFI of CD44+ in MKN45. The results showed that 180 nucleotide sequences between exon 2 and exon 3 of RELA were deleted in MKN45. RELA expression significantly (P<0.001) decreased after CRISPR/Cas9 knockout. Compared to the control group, the MFI of CD44 in transfected cells significantly decreased (P <0.001). Knockout of RELA significantly decreased CD44 expression in MKN45 cells. It can be concluded that the NF-kB signaling pathway via RELA is related to CD44 expression and consequently the tumorigenesis of gastric cancer. More studies about this relationship are recommended.

Epstein-Barr Virus-Associated Lymphoepithelioma-Like Intrahepatic Cholangiocarcinoma: A Case Study and Literature Review

Lymphoepithelioma-like intrahepatic cholangiocarcinoma (LELCC) is a genetically distinct, rare subtype of intrahepatic cholangiocarcinoma. LELCCs have a strong association with Epstein-Barr virus (EBV), though the EBV associated LELCC (EBV+LELCC) carcinogenesis pathway has not been fully delineated. Only 38 cases of EBV+LELCC have been reported in the literature to date, most commonly occurring in females and Asians. Only 2 of the 38 cases are in patients with inflammatory bowel disease. In this case study, we report two cases of EBV+LELCC in male patients with inflammatory bowel disease. The first patient is a 29 year old Bangladeshi male with ulcerative colitis and primary sclerosing cholangitis. He was initially diagnosed with an intrahepatic lesion on imaging that was confirmed EBV+LELCC by biopsy. He underwent surgical resection and adjuvant chemotherapy. He is recurrence free two years after surgery. The second patient is a 70 year old American male with ulcerative colitis. He presented with fevers of unknown origin and was found to have new biliary strictures on imaging. Subsequent ERCP brushings were positive for adenocarcinoma. Patient underwent surgical resection and will undergo adjuvant chemotherapy and chemoradiation; final pathology revealed EBV+LELCC. Most published cases of patients with EBV+LELCC report increased survival when compared to patients with conventional intrahepatic cholangiocarcinoma (C-ICC); the mechanism for this observed difference, however, has yet to be elucidated. Further research is needed to characterize the clinicopathologic features of EBV+LELCC to improve outcomes for patients with this rare disease and provide insight into potential therapeutic targets for the treatment of C-ICC.

New Approach about the Signaling Crosstalk between IQGAPs/ NF- κB/IL-8 and PDCD5/p53/TRAIL Pathways that Modulate Malignant Transformation in Hepatocellular Carcinoma.

Objective:We aimed to investigate the signalling crosstalk of TNF-related apoptosis-inducing ligand, TRAIL death receptors, tumour protein p53, and programmed cell death (PDCD5) with IQGAPs. Also, we targeted the crosstalk between IQGAPs genes with decoy receptors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and interleukins -8 (IL-8) and its receptor genes in a designed model of hepatocellular carcinoma induced in male Balb/c mice. Methods:The presence of HCC was confirmed by histological and morphological alterations. In parallel to the incidence of hepatic cancer, we found lung, heart, and kidney cancer after treatment with DEN. Results:Our results show that the expression of mRNA of IQGAP1, TRAIL decoy receptors, NF-κB, and IL-8 genes was elevated in hepatocellular carcinoma, as compared to normal liver tissue, while their expression was further up-regulated by increasing the dose of diethylnitrosamine. The expression of IQGAP2, TRAIL death receptors, p53, and PDCD5 was significantly down-regulated in HCC (p˂0.05). For confirmation of gene expression, protein levels of both IQGAP1 and P53 were measured by western blot analysis, which showed that diethylnitrosamine enhanced protein expression of IQGAP1 and diminished that of p53. Conclusion:IQGAPs have a direct signaling relationship with p53, IL-8, and TRAIL family. This interaction is recognized as a key signalling pathway for hepatocellular carcinogenesis.

Understanding and Targeting the Colon Cancer Pathogenesis: A Molecular Perspective

Colorectal cancer (CRC) one of the leading cause of cancer-related deaths worldwide. With the presently available knowledge on CRC, it is understood that the underlying is a complex process. The complexity of CRC lies in aberrant activation of several cellular signaling pathways that lead to activation and progression of CRC. In this context, recent studies have pointed towards the role of developmental pathways like; hedgehog (HH), wingless-related integration site (WNT/β-catenin) and Notch pathways that play a crucial role in maintenance and homeostasis of colon epithelium. Moreover, the deregulation of these signaling pathways has also been associated with the pathogenesis of CRC. Therefore, in the search for better therapeutic options, these pathways have emerged as potential targets. The present review attempts to highlight the role of HH, WNT/β-catenin and Notch pathways in colon carcinogenesis.

Rs708113 in WNT3A-WNT9A and hepatocellular carcinoma risk.

Hepatocellular carcinoma is the most frequent primary liver malignancy and fourth most common cause of cancer-related mortality worldwide. 1 Global Burden of Disease Cancer CollaborationGlobal, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017; 3: 524-548 Crossref PubMed Scopus (2549) Google Scholar Although chronic viral hepatitis, particularly due to hepatitis B virus (HBV) infection, is the most common underlying liver disease leading to hepatocellular carcinoma in southeast Asia, alcohol-related liver disease and non-alcoholic fatty liver disease are the predominant causes in Europe and North America. Alcohol-related liver disease and non-alcoholic fatty liver disease are expected to become the leading causes of hepatocellular carcinoma in the future, with HBV and hepatitis C virus infections declining as a result of effective vaccination strategies and treatments. With few exceptions, most hepatocellular carcinoma cases in high-income countries develop in patients with established cirrhosis; alcohol-related cirrhosis is the second most common risk factor for hepatocellular carcinoma in high-income countries, 2 West J Card TR Aithal GP Fleming KM Risk of hepatocellular carcinoma among individuals with different aetiologies of cirrhosis: a population-based cohort study. Aliment Pharmacol Ther. 2017; 45: 983-990 Crossref PubMed Scopus (40) Google Scholar with an annual risk of hepatocellular carcinoma of up to 2·5%. 3 Mancebo A González-Diéguez ML Cadahía V et al. Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups. Clin Gastroenterol Hepatol. 2013; 11: 95-101 Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar Alcohol-related hepatocellular carcinoma is a complex disease, but easily discernible clinical risk factors include type 2 diabetes, obesity, and older age. 4 Llovet JM Kelley RK Villanueva A et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 7: 6 Crossref PubMed Scopus (708) Google Scholar Sequence variations in specific genes that modify the risk of alcohol-related hepatocellular carcinoma have been identified, mostly by means of candidate gene case-control studies, which either enhance or alleviate the risk of developing hepatocellular carcinoma. However, the genetic risk loci recognised until now only represent a fraction of the heritability risk, suggesting that additional genetic modulators might exist. 5 Stickel F Buch S Nischalke HD et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018; 113: 1475-1483 Crossref PubMed Scopus (56) Google Scholar The involvement of the rs738409 locus (in the gene coding for PNPLA3) is widely supported by numerous case-control studies, which show the largest effect size among all previously identified genetic risk variants. Additional loci in genes coding for TM6SF2 (rs58542926) and HSD17B13 (rs72613567:TA) were found to increase and alleviate the risk of hepatocellular carcinoma, respectively. 5 Stickel F Buch S Nischalke HD et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018; 113: 1475-1483 Crossref PubMed Scopus (56) Google Scholar , 6 Stickel F Lutz P Buch S et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology. 2020; 72: 88-102 Crossref PubMed Scopus (52) Google Scholar However, unlike in viral hepatitis-associated hepatocellular carcinoma, 7 Jiang DK Sun J Cao G et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet. 2013; 45: 72-75 Crossref PubMed Scopus (242) Google Scholar , 8 Kumar V Kato N Urabe Y et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet. 2011; 43: 455-458 Crossref PubMed Scopus (303) Google Scholar a comprehensive and hypothesis-free genome-wide study to detect risk loci that might have remained unidentified for alcohol-related hepatocellular carcinoma so far has been lacking. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association studyWNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. Full-Text PDF

Colorectal Sessile Serrated Lesion and Synchronous Neoplasm or Polyps: An Update and Critical Assessment;Analysis of 167 Consecutive Cases Undergoing Total Colonoscopy and Found 343 Polyps

Aim: Sessile serrated lesions (SSL) have the potential for malignant transformation into colorectal carcinoma (CRC), which develops via the serrated pathway of carcinogenesis. Material and Methods: Based on colonoscopy and pathology reports, all sessile serrated lesions or polyps in the risk screening group were studied at an urban medical research center between July 2018 and July 2022. We prospectively included consecutive colorectal polyps classified as a hyperplastic polyp (HP), sessile serrated lesion (SSL), traditional serrated adenoma (TSA), unclassified serrated adenoma, and synchronous neoplasm or polyp. Results: During the 48-month study period, 167 cases of sessile serrated lesions or polyps were diagnosed. In the study, 97 (58.1%) of the patients were male, 70 were female (41.9%), and the mean age was 59.74 (± 11.1). Hematoxylin-eosin preparations were available for complete analysis for 226 SSL, and 117 had synchronous adenomatous polyps or carcinomas. Approximately 88.1% of all polyps were ≤10 mm or less in diameter. There was a significant correlation between polyp size (≤10 mm) and epithelial polyps (p=0.000). In particular, polyps detected in the sigmoid colon with the rectum were relatively larger than in other locations. The sigmoid colon and rectum were the most common locations for sessile serrated lesions in our study. There was a significant association between epithelial polyps and anatomical locations (p=0.000). The distribution of all epithelial polyps was as follows; HP was the most frequently observed epithelial polyp with 57.7% (194 polyps), SSL was 6.8% (23 polyps), and TSA was 2.1% (7 polyps), unclassified serrated adenoma was 0.6% (2 cases), synchronous conventional were seen in 31% (104 polyps) of SSL or polyps, and carcinoma with polyps was detected in three (0.9%) cases Conclusions: Hyperplastic polyps are the most common sessile serrated lesions, and synchronous conventional tubular adenomas were most commonly accompanied by hyperplastic polyps. HPs were most commonly observed in the distal colon, particularly in the sigmoid colon and rectum. Future prospective studies using uniform diagnostic criteria and considering clinical outcomes are needed to make accurate decisions regarding surveillance and treatment of patients with serrated lesions.

Front Cover: Targeting AMPK Signaling by Dietary Polyphenols in Cancer Prevention

Mol. Nutr. Food Res. 2022, 66, 202100732 DOI: 10.1002/mnfr.202100732 AMPK pathway plays vital role in the energy metabolism. Recent investigations indicate that AMPK is closely related with carcinogenesis. Polyphenols can target AMPK to promote apoptosis and cell cycle arrest of cancer cells. Besides interfering with classical carcinogenesis pathways such as MAPK, polyphenol can also target AMPK to exert anti-cancer effect by affecting energy metabolism of cancer cells. The novel mechanism will enhance the understanding of polyphenols, which benefits to develop functional foods and cancer prevention. This is reported by Feijun Luo and co-workers in article number 2100732.

Modern understanding of the pathogenesis of basal cell skin cancer

The incidence of basal cell skin cancer is increasing worldwide. The initiation and progression of basal cell skin cancer is due to the interaction of environmental factors and the patient's genetic characteristics. Aberrant activation of the transmission of the Hedgehog signaling pathway is the main pathogenetic pathway of carcinogenesis.&#x0D; Since basal cell skin cancer is manifested by significant variability of morphological structure, aggressiveness and response to treatment, the disclosure of the molecular genetics of pathogenesis will become the basis for developing new approaches and increasing the effectiveness of treatment, as well as overcoming tumor resistance to treatment.&#x0D; To search for the necessary literature, the PubMed, MedLine, Web of Science and RSCI databases were used.

Influence of retroelements on oncogenes and tumor suppressors in carcinogenesis: A review

Analysis of scientific literature data has revealed several ways in which retrotransposons, when activated, are involved in carcinogenesis. First, retroelements can encode oncogenic proteins. For example, the Np9 protein is translated from HERV-K endogenous retrovirus transcript. Second, retroelements are used as alternative promoters of protooncogenes. Accordingly, their activation contributes to the enhanced expression of oncogenes (e.g. CSF1R, IRF5, MET, RAB3IP, CHRM3). Third, retroelements are located in the introns of some genes, and upon their activation, they form chimeric transcripts, such as LTR2-FABP7, LTR-ALK, LTR-ERBB4, LINE1-MET, which have pronounced oncogenic activity. Fourth, retroelements are transposed into tumor suppressor genes (e.g. APC, NF1, MSH2, PTEN, RB1, TSC2, STK11, VHL) and inactivate them, which is associated with the presence of hot spots of insertional mutagenesis in them. As a result, the growth of tumors and the survival of their cells are stimulated. It is important to note that protein products of tumor suppressor genes, such as TP53, RB1, VHL, BRCA1, ATM, are characterized by the ability to inhibit the activity of retroelements. Accordingly, when even one oncosuppressive gene is inactivated, a kind of "vicious circle" can be triggered when the control of expression of retroelements is weakened. The latter, in turn, inactivate other tumor suppressors containing hot spots of insertional mutagenesis. This stimulates new pathways of carcinogenesis and the production of oncogenes associated with transposons. Thus, it is possible to explain in a new way the mechanisms of tumor formation in hereditary tumor syndromes. This is due to the fact that the weakening of the function of an oncosuppressor in a germinal heterozygous mutation may be sufficient to trigger a vicious circle involving retroelements, oncogenes and other oncosuppressors. Similar mechanisms are likely for sporadic malignant tumors. However, the initiating event in them can be the direct activation of transposons under the influence of stressors, chemical and physical carcinogens. In addition to the events described, activation of retroelements causes genomic instability, which contributes to complex genomic rearrangements often observed in malignant tumors. MicroRNAs and long noncoding RNAs, the sources of which are retroelements, also play an important role in the evolution of tumors. Their study is promising for the development of targeted therapy for neoplasms.

A Case of Microsatellite Instability–High Colon Cancer in a Young Woman With Familial Adenomatous Polyposis

Two major molecular pathways of colorectal carcinogenesis, chromosomal instability (CIN) and microsatellite instability (MSI), are considered to be mutually exclusive. Distinguishing CIN from MSI-high tumors has considerable therapeutic implications, because patients with MSI-high tumors can derive considerable benefit from immune checkpoint inhibitors, and tumors that evolved through the CIN pathway do not respond to these agents. Familial adenomatous polyposis (FAP) is a genetic syndrome that is defined by a mutation in the APC gene and is thought to lead to carcinogenesis through the CIN pathway. Here, we report a case of a young woman with FAP who was treated for medulloblastoma as a child and developed advanced MSI-high colon cancer as a young adult. Her response to second-line immunotherapy enabled resection of her colon cancer, and she is free of disease >10 months after surgery. This case highlights the potential for overlap between the CIN and MSI carcinogenic pathways and associated therapeutic implications.

Low-Coverage Whole Genome Sequencing Using Laser Capture Microscopy with Combined Digital Droplet PCR: An Effective Tool to Study Copy Number and Kras Mutations in Early Lung Adenocarcinoma Development.

Defining detailed genomic characterization of early tumor progression is critical to identifying key regulators and pathways in carcinogenesis as potentially druggable targets. In human lung cancer, work to characterize early cancer development has mainly focused on squamous cancer, as the earliest lesions are more proximal in the airways and often accessible by repeated bronchoscopy. Adenocarcinomas are typically located distally in the lung, limiting accessibility for biopsy of pre-malignant and early stages. Mouse lung cancer models recapitulate many human genomic features and provide a model for tumorigenesis with pre-malignant atypical adenomatous hyperplasia and in situ adenocarcinomas often developing contemporaneously within the same animal. Here, we combined tissue characterization and collection by laser capture microscopy (LCM) with digital droplet PCR (ddPCR) and low-coverage whole genome sequencing (LC-WGS). ddPCR can be used to identify specific missense mutations in Kras (Kirsten rat sarcoma viral oncogene homolog, here focused on Kras Q61) and estimate the percentage of mutation predominance. LC-WGS is a cost-effective method to infer localized copy number alterations (CNAs) across the genome using low-input DNA. Combining these methods, the histological stage of lung cancer can be correlated with appearance of Kras mutations and CNAs. The utility of this approach is adaptable to other mouse models of human cancer.

TAK1: A Molecular Link Between Liver Inflammation, Fibrosis, Steatosis, and Carcinogenesis.

Chronic insult and persistent injury can cause liver inflammation, fibrosis, and carcinogenesis; it can also be associated with metabolic disorders. Identification of critical molecules that link the process of inflammation and carcinogenesis will provide prospective therapeutic targets for liver diseases. Rapid advancements in gene engineering technology have allowed the elucidation of the underlying mechanism of transformation, from inflammation and metabolic disorders to carcinogenesis. Transforming growth factor-β-activated kinase 1 (TAK1) is an upstream intracellular protein kinase of nuclear factor kappa-B (NF-κB) and c-Jun N-terminal kinases, which are activated by numerous cytokines, growth factors, and microbial products. In this study, we highlighted the functional roles of TAK1 and its interaction with transforming growth factor-β, WNT, AMP-activated protein kinase, and NF-κB signaling pathways in liver inflammation, steatosis, fibrosis, and carcinogenesis based on previously published articles.

Therapeutic role of flavonoids and flavones in cancer prevention: Current trends and future perspectives

Cancer is one of notorious diseases across the globe.Therapeutic approaches for cancer are often expensive and develop severe side effects, and usually result comorbidities among the cancer survivors. Identifying novel therapies for treatment will reduce comorbidities in curing these diseases. It has been reported that flavones, a sub-class of flavonoid can act as a potent anticancer agent. Many experimental results displayed that flavones modulate signal transduction pathways in carcinogenesis. Flavones have been found to control cell cycle progression, oxidative stress, angiogenesis and metastasis alongwith some molecular pathways that ultimately prevent the progression of the diseases. Flavones have shown to possess a considerable as cancer preventive agents. As per the reports, flavones rich diet is beneficial, decreased risk of breast cancer, skin, digestive system, certain hematological malignancies and prostate cancer. Apart from cancer, flavones are also effective in improving other disease conditions such as cardiovascular and neurological diseases. Hence, these are the prime target in natural product and drug discovery research. Based on existing findings, it can concluded that more extensive research is needed to understand detailed beneficial properties of flavones along with biochemical mechanisms that drive these medicinal properties.

P60.02 Polymorphisms of APE1(T444G), hOGG1(C977G), XRCC1(G839A), XPD(T2251G), XPG(G3310C), XPC(A2815C) Genes in Lung Cancer Patients

Lung cancer (LC) the leading cause of cancer deaths in males for decades, has recently become one of commonest causes for women too. The DNA repair system is the first barrier in the onset pathway of genomic instability and carcinogenesis under the effect of mutagens. As has been shown in some studies, genetic polymorphisms of the DNA repair system are associated with the risk of LC development (Cai et al.,2014; Liu et al., 2017; Zhou et al.,2015).

Progressive alteration of DNA methylation of Alu, MGMT, MINT2, and TFPI2 genes in colonic mucosa during colorectal cancer development.

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is characterized by different pathways of carcinogenesis and is a heterogeneous disease with diverse molecular landscapes that reflect histopathological and clinical information. Changes in the DNA methylation status of colon epithelial cells have been identified as critical components in CRC development and appear to be emerging biomarkers for the early detection and prognosis of CRC. To explore the underlying disease mechanisms and identify more effective biomarkers of CRC. We compared the levels and frequencies of DNA methylation in 11 genes (Alu, APC, DAPK, MGMT, MLH1, MINT1, MINT2, MINT31, p16, RGS6, and TFPI2) in colorectal cancer and its precursor adenomatous polyp with normal tissue of healthy subjects using pyrosequencing and then evaluated the clinical value of these genes. Aberrant methylation of Alu, MGMT, MINT2, and TFPI2 genes was progressively accumulated during the normal-adenoma-carcinoma progression. Additionally, CGI methylation occurred either as an adenoma-associated event for APC, MLH1, MINT1, MINT31, p16, and RGS6 or a tumor-associated event for DAPK. Moreover, relatively high levels and frequencies of DAPK, MGMT, and TFPI2 methylation were detected in the peritumoral nonmalignant mucosa of cancer patients in a field-cancerization manner, as compared to normal mucosa from healthy subjects. This study identified several biomarkers associated with the initiation and progression of CRC. As novel findings, they may have important clinical implications for CRC diagnostic and prognostic applications. Further large-scale studies are needed to confirm these findings.