Department Of Human Genetics And Molecular Medicine
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Item Melittin: a possible regulator of cancer proliferation in preclinical cell culture and animal models(Springer Science and Business Media Deutschland GmbH, 2023-11-03T00:00:00) Haque, Shafiul; Hussain, Arif; Joshi, Hemant; Sharma, Ujjawal; Sharma, Bunty; Aggarwal, Diwakar; Rani, Isha; Ramniwas, Seema; Gupta, Madhu; Tuli, Hardeep SinghBackground: Melittin is a water-soluble cationic peptide derived from bee venom that has been thoroughly studied for the cure of different cancers. However, the unwanted interactions of melittin produce hemolytic and cytotoxic effects that hinder their therapeutic applications. To overcome the shortcomings, numerous research groups have adopted different approaches, including conjugation with tumor-targeting proteins, gene therapy, and encapsulation in nanoparticles, to reduce the non-specific cytotoxic effects and potentiate their anti-cancerous activity. Purpose: This article aims to provide mechanistic insights into the chemopreventive activity of melittin and its nanoversion in combination with standard anti-cancer drugs for the treatment of cancer. Methods: We looked over the pertinent research on melittin's chemopreventive properties in online databases such as PubMed and Scopus. Conclusion: In the present article, the anti-cancerous effects of melittin on different cancers have been discussed very nicely, as have their possible mechanisms of action to act against different tumors. Besides, it interacts with different signal molecules that regulate the diverse pathways of cancerous cells, such as cell cycle arrest, apoptosis, metastasis, angiogenesis, and inflammation. We also discussed the recent progress in the synergistic combination of melittin with standard anti-cancer drugs and a nano-formulated version of melittin for targeted delivery to improve its anticancer potential. Graphical abstract: [Figure not available: see fulltext.] � 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Item Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood�brain barrier and treatment strategies(Springer Science and Business Media Deutschland GmbH, 2023-03-10T00:00:00) Chhichholiya, Yogita; Ruthuparna, Malayil; Velagaleti, Harini; Munshi, AnjanaBreast cancer�(BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis�(BM) reported in 17�20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood�brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC. The therapeutic strategies being used currently and the novel ones being explored to control BM in BC have also been discussed at length. � 2023, The Author(s), under exclusive licence to Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).Item Molecular mechanisms behind ROS regulation in cancer: A balancing act between augmented tumorigenesis and cell apoptosis(Springer Science and Business Media Deutschland GmbH, 2022-11-28T00:00:00) Tuli, Hardeep Singh; Kaur, Jagjit; Vashishth, Kanupriya; Sak, Katrin; Sharma, Ujjawal; Choudhary, Renuka; Behl, Tapan; Singh, Tejveer; Sharma, Sheetu; Saini, Adesh K.; Dhama, Kuldeep; Varol, Mehmet; Sethi, GautamROS include hydroxyl radicals (HO.), superoxide (O2.), and hydrogen peroxide (H2O2). ROS are typically produced under physiological conditions and play crucial roles in living organisms. It is known that ROS, which are created spontaneously by cells through aerobic metabolism in mitochondria, can have either a beneficial or detrimental influence on biological systems. Moderate levels of ROS can cause oxidative damage to proteins, DNA and lipids, which can aid in the pathogenesis of many disorders, including cancer. However, excessive concentrations of ROS can initiate programmed cell death in cancer. Presently, a variety of chemotherapeutic drugs and herbal agents are being investigated to induce ROS-mediated cell death in cancer. Therefore, preserving ROS homeostasis is essential for ensuring normal cell development and survival. On account of a significant association of ROS levels at various concentrations with carcinogenesis in a number of malignancies, further studies are needed to determine the underlying molecular mechanisms and develop the possibilities for intervening in these processes. � 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Item Differential molecular mechanistic behavior of HDACs in cancer progression(Springer, 2022-08-16T00:00:00) Singh, Tashvinder; Kaur, Prabhsimran; Singh, Paramdeep; Singh, Sandeep; Munshi, AnjanaGenetic aberration including mutation in oncogenes and tumor suppressor genes transforms normal cells into tumor cells. Epigenetic modifications work concertedly with genetic factors in controlling cancer development. Histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and chromatin structure modifier are prospective epigenetic regulators. Specifically, HDACs are histone modifiers regulating the expression of genes implicated in cell survival, growth, apoptosis, and metabolism. The majority of HDACs are highly upregulated in cancer, whereas some have a varied function and expression in cancer progression. Distinct HDACs have a positive and negative role in controlling cancer progression. HDACs are also significantly involved in tumor cells acquiring metastatic and angiogenic potential in order to withstand the anti-tumor microenvironment. HDACs� role in modulating metabolic genes has also been associated with tumor development and survival. This review highlights and discusses the molecular mechanisms of HDACs by which they regulate cell survival, apoptosis, metastasis, invasion, stemness potential, angiogenesis, and epithelial to mesenchymal transitions (EMT) in tumor cells. HDACs are the potential target for anti-cancer drug development and various inhibitors have been developed and FDA approved for a variety of cancers. The primary HDAC inhibitors with proven anti-cancer efficacy have also been highlighted in this review. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item High levels of unfolded protein response component CHAC1 associates with cancer progression signatures in malignant breast cancer tissues(Springer Science and Business Media Deutschland GmbH, 2022-08-05T00:00:00) Mehta, Vikrant; Suman, Prabhat; Chander, HarishPurpose: The aberrant mRNA expression of a UPR component Cation transport regulator homolog 1 (CHAC1) has been reported to be associated with poor survival in breast and ovarian cancer patients, however, the expression of CHAC1 at protein levels in malignant breast tissues is underreported. The following study aimed at analyzing CHAC1 protein expression in malignant breast cancer tissues. Methods: Evaluation of CHAC1 expression in invasive ductal carcinomas (IDCs) with known ER, PR, and HER2 status was carried out using immunohistochemistry (IHC) with CHAC1 specific antibody. The Human breast cancer tissue microarray (TMA, cat# BR1503f, US Biomax, Inc., Rockville, MD) was used to determine CHAC1 expression. The analysis of CHAC1 IHC was done to determine its expression in terms of molecular subtypes of breast cancer, lymph node status, and proliferation index using Qu-Path software. Survival analysis was studied with a Kaplan�Meier plotter. Results: Immunohistochemical analysis of CHAC1 in breast cancer tissues showed significant up-regulation of CHAC1 as compared to the adjacent normal and benign tissues. Interestingly, CHAC1 immunostaining revealed high expression in tumor tissues with high proliferation and positive lymph node metastasis suggesting that CHAC1 might have an important role to play in breast cancer progression. Furthermore, high CHAC1 expression is associated with poor overall survival (OS) in large breast cancer patient cohorts. Conclusion: As a higher expression of CHAC1 was observed in tissue cores with high Ki67 index and positive lymph node metastasis it may be concluded that enhanced CHAC1 expression correlates with proliferation and metastasis. The further analysis of breast cancer patients� survival data through KM plot indicated that high CHAC1 expression is associated with a bad prognosis hinting that CHAC1 may have a possible prognostic significance in breast cancer. � 2022, The Author(s), under exclusive licence to Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).Item Prognostic significance of CHAC1 expression in breast cancer(Springer Science and Business Media B.V., 2022-06-21T00:00:00) Mehta, Vikrant; Meena, Jaipal; Kasana, Harit; Munshi, Anjana; Chander, HarishBackground: An emerging component of Unfolded Protein Response (UPR) pathway, cation transport regulator homolog 1 (CHAC1) has been conferred with the ability to degrade intracellular glutathione and induce apoptosis, however, many reports have suggested a role of CHAC1 in cancer progression. Our study aimed to investigate CHAC1 mRNA levels in large breast cancer datasets using online tools and both mRNA and protein levels in different breast cancer cell lines. Methods and results: Analysis of clinical information from various online tools (UALCAN, GEPIA2, TIMER2, GENT2, UCSCXena, bcGenExMiner 4.8, Km Plotter, and Enrichr) was done to elucidate the CHAC1 mRNA expression in large breast cancer patient dataset and its correlation with disease progression. Later, in vitro techniques were employed to explore the mRNA and protein expression of CHAC1 in breast cancer cell lines. Evidence from bioinformatics analysis as well as in vitro studies indicated a high overall expression of CHAC1 in breast tumor samples and had a significant impact on the prognosis and survival of patients. Enhanced CHAC1 levels in the aggressive breast tumor subtypes such as Human Epidermal growth factor receptor 2 (HER2) and Triple Negative Breast Cancer (TNBC) were evident. Our findings hint toward the possible role of CHAC1 in facilitating the aggressiveness of breast cancer and the disease outcome. Conclusion: In summary, CHAC1 is constantly up-regulated in breast cancer leading to a poor prognosis. CHAC1, therefore, could be a promising candidate in the analysis of breast cancer diagnosis and prognosis. � 2022, The Author(s), under exclusive licence to Springer Nature B.V.Item Long non-coding RNAs involved in different steps of cancer metastasis(Springer Science and Business Media Deutschland GmbH, 2022-02-04T00:00:00) Suman, P.; Chhichholiya, Y.; Kaur, P.; Ghosh, S.; Munshi, A.Non-proteincoding transcripts bearing 200 base pairs known as long non-coding RNAs (lncRNAs) play a role in a variety of molecular mechanisms, including cell differentiation, apoptosis and metastasis. Previous studies have suggested that frequently dysregulated lncRNAs play a crucial role in various aspects of cancer metastasis. Metastasis is the main leading cause of death in cancer. The role of lncRNAs in different stages of metastasis is the subject of this review. Based on in vitro and in vivo investigations on metastasis, we categorized lncRNAs into distinct stages of metastasis including angiogenesis, invasion, intravasation, survival in circulation, and extravasation. The involvement of lncRNAs in angiogenesis and invasion has been extensively studied. Here, we comprehensively discuss the role and functions of these lncRNAs with a particular focus on the molecular mechanisms. � 2022, The Author(s), under exclusive licence to Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).Item The genomic architecture of metastasis in breast cancer: focus on mechanistic aspects, signalling pathways and therapeutic strategies(Springer, 2021-07-16T00:00:00) Chhichholiya, Yogita; Suman, Prabhat; Singh, Sandeep; Munshi, AnjanaBreast cancer is a multifactorial, heterogeneous disease and the second most frequent cancer amongst women worldwide. Metastasis is one of the most leading causes of death in these patients. Early-stage or locally advanced breast cancer is limited to the breast or nearby lymph nodes. When breast cancer spreads to farther tissues/organs from its original site, it is referred to as metastatic or stage IV breast cancer. Normal breast development is regulated by specific genes and signalling pathways controlling cell proliferation, cell death, cell differentiation and cell motility. Dysregulation of genes involved in various signalling pathways not only leads to the formation of primary tumour but also to the metastasis as well. The metastatic cascade is represented by a multi-step process including invasion of the local tumour cell followed by its entry into the vasculature, exit of malignant cells from the circulation and ultimately their colonization at the distant sites. These stages are referred to as formation of primary tumour, angiogenesis, invasion, intravasation and extravasation, respectively. The major sites of metastasis of breast cancer are the lymph nodes, bone, brain and lung. Only about 28% five-year survival rate has been reported for stage IV breast cancer. Metastasis is a serious concern for breast cancer and therefore, various therapeutic strategies such as tyrosine kinase inhibitors have been developed to target specific dysregulated genes and various signalling pathways involved in different steps of metastasis. In addition, other therapies like hyperbaric oxygen therapy, RNA interference and CRISPR/Cas9 are also being explored as novel strategies to cure the stage IV/metastatic breast cancer. Therefore, the current review has been compiled with an aim to evaluate the genetic basis of stage IV breast cancer with a focus on the molecular mechanisms. In addition, the therapeutic strategies targeting these dysregulated genes involved in various signalling pathways have also been discussed. Genome editing technologies that can target specific genes in the affected areas by making knock-in and knock-out alternations and thereby bring significant treatment outcomes in breast cancer have also been summarized. � 2021, Springer Science+Business Media, LLC, part of Springer Nature.Item Complex roles of discoidin domain receptor tyrosine kinases in cancer(Springer Science and Business Media Deutschland GmbH, 2021-02-25T00:00:00) Mehta, V.; Chander, H.; Munshi, A.Discoidin domain receptors, DDR1 and DDR2 are members of the receptor tyrosine kinase (RTK) family that serves as a non-integrin collagen receptor and were initially identified as critical regulators of embryonic development and cellular homeostasis. In recent years, numerous studies have focused on the role of these receptors in disease development, in particular, cancer where they have been reported to augment ECM remodeling, invasion, drug resistance to facilitate tumor progression and metastasis. Interestingly, accumulating evidence also suggests that DDRs promote apoptosis and suppress tumor progression in various human cancers due to which their functions in cancer remain ill-defined and presents a case of an interesting therapeutic target. The present review has discussed the role of DDRs in tumorigenesis and the metastasis. � 2021, Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).Item KIBRA Team Up with Partners to Promote Breast Cancer Metastasis(Springer, 2019) Singh G; Mishra, S; Chander, HarishAmong women, breast cancer is the most frequently diagnosed cancer. Most of the breast cancers represent metastasis to distant organs at the time of diagnosis and accounts for the majority of deaths. Metastasis is characterized by many genetic aberrations including mutations, overexpression of oncogenes etc. KIBRA (KIdney/BRAin protein), a scaffolding protein is recently described as an important player in the process of invasion and metastasis. The Kidney/BRAin protein through its different domains interacts with various proteins to couple cytoskeleton arrangement, cell polarity and migration. N terminal and C terminal of the protein contains the WW, Internal C 2 & putative class III PDZ domain that interacts with DDR1, DLC1 & PKCζ. These protein-protein interactions equip the breast cancer cells to invade and metastasize. Here, we discuss a comprehensive knowledge about the KIBRA protein, its domains and the interacting partners involved in metastasis of breast cancer. © 2019, Arányi Lajos Foundation.