Unravelling the Mysteries of the Sonic Hedgehog Pathway in Cancer Stem Cells: Activity, Crosstalk and Regulation.

The Sonic Hedgehog (Shh) signalling pathway plays a critical role in normal development and tissue homeostasis, guiding cell differentiation, proliferation, and survival. Aberrant activation of this pathway, however, has been implicated in the pathogenesis of various cancers, largely due to its role in regulating cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells with the ability to self-renew, differentiate, and initiate tumour growth, contributing significantly to tumorigenesis, recurrence, and resistance to therapy. This review focuses on the intricate activity of the Shh pathway within the context of CSCs, detailing the molecular mechanisms through which Shh signalling influences CSC properties, including self-renewal, differentiation, and survival. It further explores the regulatory crosstalk between the Shh pathway and other signalling pathways in CSCs, highlighting the complexity of this regulatory network. Here, we delve into the upstream regulators and downstream effectors that modulate Shh pathway activity in CSCs. This review aims to cast a specific focus on the role of the Shh pathway in CSCs, provide a detailed exploration of molecular mechanisms and regulatory crosstalk, and discuss current and developing inhibitors. By summarising key findings and insights gained, we wish to emphasise the importance of further elucidating the interplay between the Shh pathway and CSCs to develop more effective cancer therapies.

Cancer and HIV: The Molecular Mechanisms of the Deadly Duo.

The immune deficiency associated with human immunodeficiency virus (HIV) infection causes a distinct increased risk of developing certain cancer types. Kaposi sarcoma (KS), invasive cervical cancer and non-Hodgkin's lymphoma (NHL) are the prominent malignancies that manifest as a result of opportunistic viral infections in patients with advanced HIV infection. Despite the implementation of antiretroviral therapy (ART), the prevalence of these acquired immunodeficiency syndrome (AIDS)-defining malignancies (ADMs) remains high in developing countries. In contrast, developed countries have experienced a steady decline in the occurrence of these cancer types. However, there has been an increased mortality rate attributed to non-ADMs. Here, we provide a review of the molecular mechanisms that are responsible for the development of ADMs and non-ADMs which occur in HIV-infected individuals. It is evident that ART alone is not sufficient to fully mitigate the potential for ADMs and non-ADMs in HIV-infected individuals. To enhance the diagnosis and treatment of both HIV and malignancies, a thorough comprehension of the mechanisms driving the development of such cancers is imperative.

Epigenetic regulation in colorectal cancer: The susceptibility of microRNAs 145, 143 and 133b to DNA demethylation and histone deacetylase inhibitors.

Globally, colorectal cancer (CRC) is a major health concern. Despite improvements in CRC treatment, mortality rates remain high. Genetic instability and epigenetic dysregulation of gene expression are instigators of CRC development that result in genotypic differences, leading to often variable and unpredictable treatment responses. Three miRNAs, miR-143, -145 and -133b, are most commonly downregulated in CRC and are proposed here as potential tumour suppressors. Although the downregulation of these miRNAs in CRC is largely unexplained, epigenetic silencing has been postulated to be a causative regulatory mechanism. Potential epigenetic modulation of miRNA expression, by means of histone acetylation and DNA methylation, was assessed in this study by treating early (SW1116) and late stage (DLD1) CRC cells with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-Aza-2'C) and the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), respectively. Subsequent quantification of miRNA expression revealed that while all the selected miRNAs were susceptible to DNA demethylation in early- and late-stage CRC cells, susceptibility to DNA demethylation was significantly pronounced in late-stage DLD1 cells. Conversely, although histone acetylation moderately affected miRNA expression in early-stage CRC, it had a marginal effect on the expression of miRNAs in late-stage CRC cells. Overall, this study provides further understanding of the contribution of epigenetics to the regulation of putative tumour suppressor miRNAs in CRC.

Computational Analysis of miRNA and their Gene Targets Significantly Involved in Colorectal Cancer Progression.

BACKGROUND: Globally, colorectal cancer (CRC) is the third most common cancer in women and the fourth most common cancer in men. Dysregulation of small non-coding miRNAs have been correlated with colon cancer progression. Since there are increasing reports of candidate miRNAs as potential biomarkers for CRC, this makes it important to explore common miRNA biomarkers for colon cancer. As computational prediction of miRNA targets is a critical initial step in identifying miRNA: mRNA target interactions for validation, we aim here to construct a potential miRNA network and its gene targets for colon cancer from previously reported candidate miRNAs, inclusive of 10 up- and 9 down-regulated miRNAs from tissues; and 10 circulatory miRNAs. METHODS: The gene targets were predicted using DIANA-microT-CDS and TarBaseV7.0 databases. Each miRNA and its targets were analyzed further for colon cancer hotspot genes, whereupon DAVID analysis and mirPath were used for KEGG pathway analysis. RESULTS: We have predicted 874 and 157 gene targets for tissue and serum specific miRNA candidates, respectively. The enrichment of miRNA revealed that particularly hsa-miR-424-5p, hsa-miR-96-5p, hsa-miR-1290, hsa-miR-224, hsa-miR-133a and has-miR-363-3p present possible targets for colon cancer hallmark genes, including BRAF, KRAS, EGFR, APC, amongst others. DAVID analysis of miRNA and associated gene targets revealed the KEGG pathways most related to cancer and colon cancer. Similar results were observed in mirPath analysis. A new insight gained in the colon cancer network pathway was the association of hsa-mir-133a and hsa-mir-96-5p with the PI3K-AKT signaling pathway. In the present study, target prediction shows that while hsa-mir-424-5p has an association with mostly 10 colon cancer hallmark genes, only their associations with MAP2 and CCND1 have been experimentally validated. CONCLUSION: These miRNAs and their targets require further evaluation for a better understanding of their associations, ultimately with the potential to develop novel therapeutic targets.

Anti-LRP/LR-specific antibody IgG1-iS18 significantly reduces adhesion and invasion of metastatic lung, cervix, colon and prostate cancer cells.

The 37-kDa/67-kDa laminin receptor [laminin receptor precursor/high-affinity laminin receptor (LRP/LR)] is thought to play a major role in invasion and adhesion, key components of metastatic cancer. Lung cancer, cervical cancer, colon cancer and prostate cancer are among the top 10 cancer types worldwide. Here, we report that LRP/LR levels on the surface of lung cancer cells, cervical cancer cells, colon cancer cells and prostate cancer cells are significantly increased compared to non-tumorigenic fibroblasts. Adhesion of lung cancer cells, cervical cancer cells, colon cancer cells and prostate cancer cells to laminin-1 is significantly reduced, employing the anti-LRP/LR-specific antibody IgG1-iS18. Invasion of these cell lines into the Matrigel™ matrix was significantly impeded with IgG1-iS18. The Pearson's correlation coefficient proves a correlation between LRP/LR cell-surface levels and invasion potential, as well as adhesion and invasion, respectively. Our findings suggest that IgG1-iS18 antibody might act as alternative therapeutic tool for treatment of various metastatic cancer types.

Patented biological approaches for the therapeutic modulation of the 37 kDa/67 kDa laminin receptor.

IMPORTANCE OF THE FIELD: The 37/67 kDa laminin receptor precursor/laminin receptor (LRP/LR) represents a multifunctional protein located on the cell surface, in the cytosol and the nucleus. The receptor acts as a mediator for cell adhesion, cell proliferation and cell differentiation. It is a key player in invasion and adhesion, major functions of several important metastatic cancer types. The receptor hampers apoptosis thereby favoring cancer progression. LRP/LR plays a major role as a cell surface receptor in prion disorders and may be of considerable importance for other neurodegenerative diseases such as Alzheimer's disease. A series of viruses including Sindbis virus, Dengue virus and Adeno-associated virus use LRP/LR as attachment receptors. Bacteria and Candida albicans use the receptor for pathogenesis. AREAS COVERED IN THIS REVIEW: Background and patented biological approaches for therapeutic modulation of LRP/LR in neurodegenerative diseases, cancer, viral disorders, bacterial and yeast infections. WHAT THE READER WILL GAIN: A comprehensive review of the role of LRP/LR in infectious and non-infectious diseases and an insightful assessment of published or patented biological approaches for the therapeutic modulation of LRP/LR. TAKE HOME MESSAGE: Molecular tools such as antibodies directed against LRP/LR have the potential to act as promising alternative therapeutics for the treatment of various diseases.

Interactions between PrP(c) and other ligands with the 37-kDa/67-kDa laminin receptor.

The 37-kDa/67 kDa laminin receptor (LRP/LR) represents a multifunctional protein. It is a receptor for viruses such as Dengue viruses, Alphaviruses and Adeno-associated viruses (AAV), as well as the cellular prion protein (PrPc) and infectious prions. Furthermore, the 37-kDa/67-kDa LRP/LR plays fundamental roles in basic cell biological processes such as cell adhesion and cell growth and acts as a key player in metastatic cancer, affecting invasion, adhesion and apoptotic processes. This review gives fundamental insights into basic cellular processes affected by LRP/LR including signal transduction and cell cycle progression and focuses on pathophysiological implications of the interaction of prion proteins, laminin, viruses and other ligands with LRP/LR affecting the development of highly-prevalent diseases such as cancer, neurodegenerative diseases such as prion disorders and Alzheimer's disease as well as viral infections. Molecular tools such as LRP/LR specific antibodies and siRNAs targeting LRP expression as possible alternative therapeutics for the treatment of neurodegenerative diseases, metastatic cancer and viral infections are emphasized.