Molecular aspects of ABCB1 and ABCG2 in Gallbladder cancer and its clinical relevance.

The function of ABC transporters in the body is manifold; such as maintenance of homeostasis, effect on multi-drug resistance and their role in tumor initiation & progression. Evidence pointing towards the direct or indirect role of ABC transporter genes in particular; ABCB1 and ABCG2 in cancer genesis is increasing. However, their role in gallbladder cancer is unexplored. Therefore, we investigated the methylation status and expression pattern of ABCB1 and ABCG2in gallbladder carcinogenesis. The methylation and expression study of ABCB1/MDR1 and ABCG2/BCRP was performed in tumour and normal fresh tissue samples collected from 61 histopathologically diagnosed gallbladder cancer patients. The methylation status was analysed by Methylation-Specific PCR and expression was determined by Real-Time PCR and Immunohistochemistry. Hypomethylation of ABCB1 and ABCG2 was found in 44 (72.13%) and 48 (78.6%) cases, respectively. ABCB1 hypomethylation pattern showed association with female patients (p = 0.040) and GradeII tumors (p = 0.036) while, ABCG2 hypomethylation was more frequent in early tumors (T1-T2). The mRNA expression ofABCB1 and ABCG2 was up-regulated in 33 (54.10%) and 41 (67.21%) patients with fold change of 4.7 and 5.5, respectively. The mRNA expression of both genes showed association with Grade II tumours and the increased fold change of ABCG2 was higher in (T1-T2) depth of invasion (p = 0.02) and Stage I-II disease (p = 0.08). The protein expression on IHC was strongly positive for ABCB1/MDR1and ABCG2/BCRP in 32 (52.46%) and 45 (73.77%) patients, respectively. The protein expression in ABCG2 showed association with patients age > 50 years (p = 0.04) and GradeII differentiation (p = 0.07). Interestingly, the hypomethylation of both the genes showed significant correlation with increased expression. ABCB1/MDR1 and ABCG2/BCRP hypomethylation and overexpression could have a potential role in gallbladder cancer tumorigenesis especially in early stages. The epigenetic change might be a plausible factor for altered gene expression of ABCB1 and ABCG2 in gallbladder cancer.

Ligand decorated biodegradable nanomedicine in the treatment of cancer.

Cancer is one of the major global health problems, responsible for the second-highest number of deaths. The genetic and epigenetic changes in the oncogenes or tumor suppressor genes alter the regulatory pathways leading to its onset and progression. Conventional methods are used in appropriate combinations for the treatment. Surgery effectively treats localized tumors; however, it fails to treat metastatic tumors, leading to a spread in other organs, causing a high recurrence rate and death. Among the different strategies, the nanocarriers-based approach is highly sought for, but its nonspecific delivery can cause a profound side effect on healthy cells. Targeted nanomedicine has the advantage of targeting cancer cells specifically by interacting with the receptors overexpressed on their surface, overcoming its non-specificity to target healthy cells. Nanocarriers prepared from biodegradable and biocompatible materials are decorated with different ligands by encapsulating therapeutic or diagnostic agents or both to target cancer cells overexpressing the receptors. Scientists are now utilizing a theranostic approach to simultaneously evaluate nanocarrier bio-distribution and its effect on the treatment regime. Herein, we have summarized the recent 5-year efforts in the development of the ligands decorated biodegradable nanocarriers, as a targeted nanomedicine approach, which has been highly promising in the treatment of cancer.

Elevated expression of RUNX3 co-expressing with EZH2 in esophageal cancer patients from India.

BACKGROUND: Runt related transcription factor3 (RUNX3) is considered as a tumor suppressor gene (TSG) that functions through the TGF-ß dependent apoptosis. Promoter methylation of the CpG islands of RUNX3 and overexpression of enhancer of zeste homolog 2 (EZH2) has been suggested to downregulate RUNX3 in cancer. METHODS: Here, we studied the expression of RUNX3 and EZH2 in 58 esophageal tumors along with paired adjacent normal tissue. mRNA levels, protein expressions and cellular localizations of EZH2 and RUNX3 were analyzed using real-time PCR and immunohistochemistry, respectively. DNA methylation was further assessed by the methylation specific-PCR. RESULTS: Compared to normal tissue, a significant increase in expression of RUNX3 mRNA in 31/57 patient's tumor tissue (p < 0.04) was observed. The expression of EZH2 was found to be upregulated compared to normal, and a significant positive correlation between EZH2 and RUNX3 expression was observed (p = 0.002). 22 of the 27 unmethylated cases at the promoter region of the RUNX3 had elevated RUNX3 protein expression (p < 0.001). CONCLUSION: The data presented in this study provide new insights into the biology of RUNX3 and highlights the need to revisit our current understanding of the role of RUNX3 in cancer.

AA genotype of cyclin D1 G870A polymorphism increases breast cancer risk: Findings of a case-control study and meta-analysis.

BACKGROUND: Cyclin D1 (CCND1) polymorphisms, a regulator of the cell cycle progress from G1 to the S phase, may lead to uncontrolled cell proliferation and lack of apoptosis. G870A, a common single-nucleotide polymorphism in CCND1 influences breast cancer risk. However, the association between G870A polymorphism and breast cancer risk is ambiguous so far. MATERIALS AND METHODS: In this case-control study, we analyzed the role of G870A polymorphism with breast cancer risk in Indian women. A meta-analysis of 18 studies was also performed to elucidate this association by increasing statistical power. RESULTS: In our case-control study, significant risk association of the CCND1 G870A AA genotype with breast cancer in total cohort (odds ratio [OR], 2.98; 95% confidence interval [CI], 1.64-5.42; P value, 4.96e-04) and premenopausal women (OR, 3.31; 95% CI, 1.54-7.08; P value, .003) was found. The results of the meta-analysis showed that AA genotype of the CCND1 G870A polymorphism significantly increases breast cancer risk in total pooled data (AA vs GG+GA: OR = 1.20; 95% CI = 1.03 to 1.39; P value, 0.016*) and Caucasian (AA vs GG+GA: OR = 1.22; 95% CI = 0.99 to 1.51; P value, .056*) but not in Asian population. Further, a significant protective association with breast cancer was also found in the GA vs AA comparison model in pooled data (OR = 0.73; 95% CI = 0.58 to 0.92; P value, .007*) as well as in Caucasian subgroup (OR = 0.62; 95% CI = 0.49 to 0.94; P value, .022*). CONCLUSION: CCND1 G870A AA genotype was found associated with breast cancer risk. Future association studies considering the environmental impact on gene expression are required to validate/explore this association.

Implication of gut microbes and its metabolites in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer with a significant impact on loss of life. In 2020, nearly 1.9 million new cases and over 9,35,000 deaths were reported. Numerous microbes that are abundant in the human gut benefit host physiology in many ways. Although the underlying mechanism is still unknown, their association appears to be crucial in the beginning and progression of CRC. Diet has a significant impact on the microbial composition and may increase the chance of getting CRC. Increasing evidence points to the gut microbiota as the primary initiator of colonic inflammation, which is connected to the development of colonic tumors. However, it is unclear how the microbiota contributes to the development of CRCs. Patients with CRC have been found to have dysbiosis of the gut microbiota, which can be identified by a decline in commensal bacterial species, such as those that produce butyrate, and a concurrent increase in harmful bacterial populations, such as opportunistic pathogens that produce pro-inflammatory cytokines. We believe that using probiotics or altering the gut microbiota will likely be effective tools in the fight against CRC treatment. PURPOSE: In this review, we revisited the association between gut microbiota and colorectal cancer whether cause or effect. The various factors which influence gut microbiome in patients with CRC and possible mechanism in relation with development of CRC. CONCLUSION: The clinical significance of the intestinal microbiota may aid in the prevention and management of CRC.

A non-invasive miRNA-based approach in early diagnosis and therapeutics of oral cancer.

Oral or mouth cancer is the 16th most common form of cancer among the world's topmost malignancies. Healthy lifestyle and control of known risk factors can reduce its incidences further. Patients succumb to oral cancer when diagnosed late and lack timely access to tertiary care. Molecular biomarkers might help in early detection of oral cancer. Recently, researchers have identified numerous microRNAs which play a crucial role in promoting and suppressing oral cancers. miRNAs are short non-coding RNA molecules (18-22 nucleotides) that play a pivotal role in regulating gene expression. Understanding the miRNA interplays in oral cancers could augment the development of potential diagnostic, prognostic, and therapeutic tools. Liquid biopsy- a non-invasive approach that has been used lately, allows the determination of miRNAs in biological fluids that play essential roles in tumor suppression and cancer promotion. Herein, we summarize an update on the role of miRNAs in the diagnosis and treatment of oral cancer.

Diagnostic and prognostic biomarkers in colorectal cancer and the potential role of exosomes in drug delivery.

Colorectal cancer (CRC) is the third most common cancer with the second most frequent cause of death worldwide. One fourth to one fifth of the CRC cases are detected at advance stage. Early detection of colorectal cancer might help in decreasing mortality and morbidity worldwide. CRC being a heterogeneous disease, new non-invasive approaches are needed to complement and improve the screening and management of CRC. Reliable and early detectable biomarkers would improve diagnosis, prognosis, therapeutic responses, and will enable the prediction of drug response and recurrence risk. Over the past decades molecular research has demonstrated the potentials of CTCs, ctDNAs, circulating mRNAs, ncRNAs, and exosomes as tumor biomarkers. Non-invasive screening approaches using fecal samples for identification of altered gut microbes in CRC is also gaining attention. Exosomes can be potential candidates that can be employed in the drug delivery system. Further, the integration of in vitro, in vivo and in silico models that involve CRC biomarkers will help to understand the interactions occurring at the cellular level. This review summarizes recent update on CRC biomarkers and their application along with the nanoparticles followed by the application of organoid culture in CRC.

S1P signaling, its interactions and cross-talks with other partners and therapeutic importance in colorectal cancer.

Sphingosine-1-Phosphate (S1P) plays an important role in normal physiology, inflammation, initiation and progression of cancer. Deregulation of S1P signaling causes aberrant proliferation, affects survival, leads to angiogenesis and metastasis. Sphingolipid rheostat is crucial for cellular homeostasis. Discrepancy in sphingolipid metabolism is linked to cancer and drug insensitivity. Owing to these diverse functions and being a potent mediator of tumor growth, S1P signaling might be a suitable candidate for anti-tumor therapy or combination therapy. In this review, with a focus on colorectal cancer we have summarized the interacting partners of S1P signaling pathway, its therapeutic approaches along with the contribution of S1P signaling to various cancer hallmarks.

Elucidation of Epigenetic Landscape in Coronary Artery Disease: A Review on Basic Concept to Personalized Medicine.

Despite extensive clinical research and management protocols applied in the field of coronary artery diseases (CAD), it still holds the number 1 position in mortality worldwide. This indicates that we need to work on precision medicine to discover the diagnostic, therapeutic, and prognostic targets to improve the outcome of CAD. In precision medicine, epigenetic changes play a vital role in disease onset and progression. Epigenetics is the study of heritable changes that do not affect the alterations of DNA sequence in the genome. It comprises various covalent modifications that occur in DNA or histone proteins affecting the spatial arrangement of the DNA and histones. These multiple modifications include DNA/histone methylation, acetylation, phosphorylation, and SUMOylation. Besides these covalent modifications, non-coding RNAs-viz. miRNA, lncRNA, and circRNA are also involved in epigenetics. Smoking, alcohol, diet, environmental pollutants, obesity, and lifestyle are some of the prime factors affecting epigenetic alterations. Novel molecular techniques such as next-generation sequencing, chromatin immunoprecipitation, and mass spectrometry have been developed to identify important cross points in the epigenetic web in relation to various diseases. The studies regarding exploration of epigenetics, have led researchers to identify multiple diagnostic markers and therapeutic targets that are being used in different disease diagnosis and management. Here in this review, we will discuss various ground-breaking contributions of past and recent studies in the epigenetic field in concert with coronary artery diseases. Future prospects of epigenetics and its implication in CAD personalized medicine will also be discussed in brief.

Cross-talk between next generation sequencing methodologies to identify genomic signatures of esophageal cancer.

The asymptomatic behaviour of esophageal cancerous cells at early stages develops advanced clinical presentation of the disease, resulting in poor prognosis and curbed intervention of therapeutic modalities. The endeavours to detect diagnostic and prognostic markers have been proven futile at the clinical platform. While several biomarkers have been investigated, including CYFRA 21-1, carcinoembryonic antigen and squamous cell carcinoma antigen, their sensitivity has not proved consistently satisfactory across the various stages of esophageal cancer. Hence, there is an impending requirement of biomarkers for early diagnosis and better prognosis. In the recent past, next generation sequencing (NGS) tool has emerged as an important tool to highlight the hallmarks of esophageal cancer (EC). This review summarizes the changes/mutations occurred in tumor cells during carcinogenesis and addresses the contribution of NGS techniques, viz. whole genome sequencing (WGS), RNA-Sequencing and Exome sequencing (ES), in EC. Additionally, this review highlights the connection between the findings from these techniques. An effort has been made to emphasize the genes affected and involved signaling pathway in EC. Further, investigations of these mutated genes would not only shed light on the relevant genes to be studied but also help in the better management and cure through personalized therapy.