64 research outputs found
Towards a Better Understanding of the Molecular Mechanisms Involved in Sunlight-Induced Melanoma
Although much less prevalent than its nonmelanoma skin cancer counterparts, cutaneous malignant melanoma (CMM) is the most lethal human skin cancer. Epidemiological and biological studies have established a strong link between lifetime exposure to ultraviolet (UV) light, particularly sunburn in childhood, and the development of melanoma. However, the specific molecular targets of this environmental carcinogen are not known. Data obtained from genetic and molecular studies over the last few years have identified the INK4a/ARF locus as the “gatekeeper” melanoma suppressor, encoding two tumour suppressor proteins in human, p16(INK4a) and p14(ARF). Recent developments in molecular biotechnology and research using laboratory animals have made a significant gene breakthrough identifying the components of the p16(INK4a)/Rb pathway as the principal and rate-limiting targets of UV radiation actions in melanoma formation. This review summarizes the current knowledge of the molecular mechanisms involved in melanoma development and its relationship to sunlight UV radiation
Towards understanding the mechanisms of actions of carcinoembryonic antigen-related cell adhesion molecule 6 in cancer progression
Human carcinoembryonic antigen (CEA) is the prototypic member of a family of
highly related cell surface glycoproteins that includes carcinoembryonic antigenrelated
cell adhesion molecule 6 (CEACAM6) and others. CEACAM6 (formerly NCA),
which belongs to the immunoglobulin superfamily, is a cell adhesion protein of the
CEA family. It is normally expressed on the epithelial surfaces and on the surface of
myeloid cells (CD66c). CEACAM6 is a multi-functional glycoprotein that mediates
homotypic binding with other CEA family members and heterotypic binding with
integrin receptors. It functions by organizing tissue architecture and regulating different
signal transduction, while aberrant expression leads to the development of
human malignancies. It was first discovered in proliferating cells of adenomas and
hyperplastic polyps in comparison to benign colonic tissue when overexpressed on
the surface of various cell types in model systems. CEACAM6 functions as a paninhibitor
of cell differentiation and cell polarization, and it also causes distortion of
tissue architecture. Moreover, overexpression of CEACAM6 modulates cancer progression
through aberrant cell differentiation, anti-apoptosis, cell growth and resistance
to therapeutic agents. In addition, CEACAM6 overexpression in multiple
malignancies promotes cell invasion and metastasis, thereby representing an
acquired advantage of tumor cells directly responsible for an invasive phenotype.
This review focuses on the findings supporting the mechanisms of actions linking
the oncogenic potential of CEACAM6 to the onset of cancer progression and pathogenesis,
especially in breast cancer, and to validating CEACAM6 as a target to pave
the way towards the design of efficient therapeutic strategies against breast cancer
Novel CD44-downstream signaling pathways mediating breast tumor invasion
CD44, also known as homing cell adhesion molecule is a multi-structural cell molecule involved in cell-cell
and cell-extracellular matrix communications. CD44 regulates a number of central signaling pathways,
including PI3K/AKT, Rho GTPases and the Ras-MAPK pathways, but also acts as a growth/arrest sensor,
and inhibitor of angiogenesis and invasion, in response to signals from the microenvironment. The
function of CD44 has been very controversial since it acts as both, a suppressor and a promoter of tumor
growth and progression. To address this discrepancy, we have previously established CD44-inducible
system both in vitro and in vivo. Next, using microarray analysis, we have identified and validated Survivin,
Cortactin and TGF-β2 as novel CD44-downstream target genes, and characterized their signaling
pathways underpinning CD44-promoted breast cancer (BC) cell invasion. This report aims to update the
literature by adding and discussing the impact of these novel three signaling pathways to better
understand the CD44-signaling pathways involved in BC tumor cell invasion
Molecular Evidence of Breast Cancer Cell Proliferation Inhibition by a Combination of Selected Qatari Medicinal Plants Crude Extracts
: Breast cancer (BC) is the most common malignancy, and conventional medicine has failed
to establish efficient treatment modalities. Conventional medicine failed due to lack of knowledge of
the mechanisms that underpin the onset and metastasis of tumors, as well as resistance to treatment
regimen. However, Complementary and Alternative medicine (CAM) modalities are currently
drawing the attention of both the public and health professionals. Our study examined the effect of a
super-combination (SC) of crude extracts, which were isolated from three selected Qatari medicinal
plants, on the proliferation, motility and death of BC cells. Our results revealed that SC attenuated
cell growth and caused the cell death of MDA-MB-231 cancer cells when compared to human
normal neonatal fibroblast cells. On the other hand, functional assays showed that SC reduced BC
cell migration and invasion, respectively. SC-inhibited cell cycle and SC-regulated apoptosis was
most likely mediated by p53/p21 pathway and p53-regulated Bax/BCL-2/Caspace-3 pathway. Our
ongoing experiments aim to validate these in vitro findings in vivo using a BC-Xenograft mouse
model. These findings support our hypothesis that SC inhibited BC cell proliferation and induced
apoptosis. These findings lay the foundation for further experiments, aiming to validate SC as
an effective chemoprevention and/or chemotherapeutic strategy that can ultimately pave the way
towards translational research/clinical trials for the eradication of BC.This research was made possible by support from the Qatar University’s-Japan Research Collaboration Grant (M-QJRC-2020-10) and the Qatar National Research Fund (UREP21-080-1-015 and UREP29-186-3-059)
Towards understanding the genetics of Autism
Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders that affect communication skills, social interaction and intellectual ability. Despite evidence suggesting a strong genetic link with ASD, the genetic determinant remains unclear. Early studies focusing on candidate genes have shown that several genes associated with neuronal synaptic function are involved in development of ASD. Linkage studies have identified several single nucleotide polymorphisms (SNPs) associated with ASD, and genome-wide association studies have implicated several loci, but failed to recognize a single specific locus with strong significance, indicating heterogeneity in ASD genetic determinants. Detection of de novo copy number variations and single nucleotide variants in several ASD probands has confirmed the genetic heterogeneity of the disease. More interestingly, next generation sequencing approaches have recently identified novel candidate genes and several point mutations in sporadic ASDs, thus increasing our knowledge of ASD etiology. The current review summarizes the findings of recent studies using genetic and genomic approaches to understand the underlying molecular mechanisms of ASD.Scopu
Novel role of BRCA1 interacting C-terminal helicase 1 (BRIP1) in breast tumour cell invasion
Breast cancer (BC) is the most common malignancy and the leading cause of death in women worldwide. Only 5%-10% of mutations in BRCA genes are associated with familial breast tumours in Eastern countries, suggesting the contribution of other genes. Using a microarray gene expression profiling study of BC, we have recently identified BRIP1 (fivefold up-regulation) as a potential gene associated with BC progression in the Omani population. Although BRIP1 regulates DNA repair and cell proliferation, the precise role of BRIP1 in BC cell invasion/metastasis has not been explored yet; this prompted us to test the hypothesis that BRIP1 promotes BC cell proliferation and invasion. Using a combination of cellular and molecular approaches, our results revealed differential overexpression of BRIP1 in different BC cell lines. Functional assays validated further the physiological relevance of BRIP1 in tumour malignancy, and siRNA-mediated BRIP1 knockdown significantly reduced BC cell motility by targeting key motility-associated genes. Moreover, down-regulation of BRIP1 expression significantly attenuated cell proliferation via cell cycle arrest. Our study is the first to show the novel function of BRIP1 in promoting BC cell invasion by regulating expression of various downstream target genes. Furthermore, these findings provide us with a unique opportunity to identify BRIP1-induced pro-invasive genes that could serve as biomarkers and/or targets to guide the design of appropriate BC targeted therapies
CD146, a novel target of CD44-signaling, suppresses breast tumor cell invasion.
We have previously validated three novel CD44-downstream positively regulated transcriptional targets, including Cortactin, Survivin and TGF-β2, and further characterized the players underlying their separate signaling pathways. In the present study, we identified CD146 as a potential novel target, negatively regulated by CD44. While the exact function of CD146 in breast cancer (BC) is not completely understood, substantial evidence from our work and others support the hypothesis that CD146 is a suppressor of breast tumor progression. Therefore, using molecular and pharmacological approaches both in vitro and in breast tissues of human samples, the present study validated CD146 as a novel target of CD44-signaling suppressed during BC progression. Our results revealed that CD44 activation could cause a substantial decrease of CD146 expression with an equally notable converse effect upon CD44-siRNA inhibition. More interestingly, activation of CD44 decreased cellular CD146 and increased soluble CD146 through CD44-dependent activation of MMP. Here, we provide a possible mechanism by which CD146 suppresses BC progression as a target of CD44-downstream signaling, regulating neovascularization and cancer cell motility
CD44 mediates stem cell mobilization to damaged lung its novel transcriptional targets, Cortactin and Survivin
Beyond their role in bone and lung homeostasis, mesenchymal stem cells (MSCs) are becoming popular in cell therapy. Various insults may disrupt the repair mechanisms involving MSCs. One such insult is smoking, which is a major risk factor for osteoporosis and respiratory diseases. Upon cigarette smoke-induced damage, a series of reparatory mechanisms ensue; one such mechanism involves Glycosaminoglycans (GAG). One of these GAGs, namely hyaluronic acid (HA), serves as a potential therapeutic target in lung injury. However, much of its mechanisms of action through its major receptor CD44 remains unexplored. Our previous studies have identified and functionally validated that both cortactin (CTTN: marker of motility) and Survivin (BIRC5: required for cell survival) act as novel HA/CD44-downstream transcriptional targets underpinning cell motility. Here, human MSCs were treated with "" smoke to investigate the effects of cigarette smoke condensate (CSC) on these HA-CD44 novel signaling pathways. Our results show that CSC decreased the expression of both CD44 and its downstream targets CTTN and BIRC5 in MSCs, and that HA reversed these effects. Interestingly, CSC inhibited migration and invasion of MSCs upon CD44-targeted RNAi treatment. This shows the importance of CD44-HA/CTTN and CD44-HA/BIRC5 signaling pathways in MSC motility, and further suggests that these signaling pathways may provide a novel mechanism implicated in migration of MSCs during repair of lung tissue injury. These findings suggest that one should use caution before utilizing MSC from donors with history of smoking, and further pave the way towards the development of targeted therapeutic approaches against CD44-associated diseases
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