Bone metastatic prostate cancer and resistance to tyrosine kinase inhibitors: an intimate relationship between loss of miR-203 and up-regulation of EGFR signaling: DOI: 10.14800/rd.345

A tumor suppressor role for miR-203 in RAS-dependent prostate cancer metastasis has been described recently by our group. We have explored the regulatory mechanisms by which miR-203 is being regulated through EGFR signaling. We investigated the molecular mechanism of metastasis and identified novel roles of genes that interact with miR-203 downstream of activated Ras. We showed an amplifying regulatory loop involving the direct interaction of miR-203 with the EGFR ligands, AREG, EREG, and TGFA 3’UTR. Using clinical specimens and database analysis, our data suggested that decreasing miR-203 and increasing EGFR ligands, AREG, EREG, and TGFA expressions are correlated with prostate cancer progression. Since tyrosine kinase inhibitors (TKIs) have been shown to inhibit tyrosine phosphorylation of EGFR in a dose-dependent manner, we examined a role for miR-203 in TKIs-induced apoptosis in RAS-activated prostate cancer. We investigated the mechanisms by which miR-203 overexpression contributes to TKIs-resistant RAS-activated prostate cancer cells apoptosis. We have shown indications for candidate miR-203 targets that are either influenced by anti-apoptotic proteins (e.g. API5, BIRC2, and TRIAP1) or positively influenced by a novel NF-?B-inducible oncogenic molecule, TNFAIP8. These observations suggest that the latter category may be synergistically affected by the regulatory loop of miR-203 depletion and anti-apoptotic proteins overexpression. Our results provided evidence showing a role of miR-203 in regulating the expression of EGFR signaling genes in response to TKIs-resistance during prostate cancer progression

Bone metastatic prostate cancer and resistance to tyrosine kinase inhibitors: an intimate relationship between loss of miR-203 and up-regulation of EGFR signaling

A tumor suppressor role for miR-203 in RAS-dependent prostate cancer metastasis has been described recently by our group. We have explored the regulatory mechanisms by which miR-203 is being regulated through EGFR signaling. We investigated the molecular mechanism of metastasis and identified novel roles of genes that interact with miR-203 downstream of activated Ras. We showed an amplifying regulatory loop involving the direct interaction of miR-203 with the EGFR ligands, AREG, EREG, and TGFA 3’UTR. Using clinical specimens and database analysis, our data suggested that decreasing miR-203 and increasing EGFR ligands, AREG, EREG, and TGFA expressions are correlated with prostate cancer progression. Since tyrosine kinase inhibitors (TKIs) have been shown to inhibit tyrosine phosphorylation of EGFR in a dose-dependent manner, we examined a role for miR-203 in TKIs-induced apoptosis in RAS-activated prostate cancer. We investigated the mechanisms by which miR-203 overexpression contributes to TKIs-resistant RAS-activated prostate cancer cells apoptosis. We have shown indications for candidate miR-203 targets that are either influenced by anti-apoptotic proteins (e.g. API5, BIRC2, and TRIAP1) or positively influenced by a novel NF-κB-inducible oncogenic molecule, TNFAIP8. These observations suggest that the latter category may be synergistically affected by the regulatory loop of miR-203 depletion and anti-apoptotic proteins overexpression. Our results provided evidence showing a role of miR-203 in regulating the expression of EGFR signaling genes in response to TKIs-resistance during prostate cancer progression

Cancer Stem Cells in Neuroblastoma: Expanding the Therapeutic Frontier

Neuroblastoma (NB) is the most common extracranial solid tumor often diagnosed in childhood. Despite intense efforts to develop a successful treatment, current available therapies are still challenged by high rates of resistance, recurrence and progression, most notably in advanced cases and highly malignant tumors. Emerging evidence proposes that this might be due to a subpopulation of cancer stem cells (CSCs) or tumor-initiating cells (TICs) found in the bulk of the tumor. Therefore, the development of more targeted therapy is highly dependent on the identification of the molecular signatures and genetic aberrations characteristic to this subpopulation of cells. This review aims at providing an overview of the key molecular players involved in NB CSCs and focuses on the experimental evidence from NB cell lines, patient-derived xenografts and primary tumors. It also provides some novel approaches of targeting multiple drivers governing the stemness of CSCs to achieve better anti-tumor effects than the currently used therapeutic agents

Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor behind the Scene

Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide, especially in countries that are undergoing rapid industrialization changes. Apparently, lifestyle risk factors including diet, physical inactivity and obesity play pivotal, yet preventable, roles in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors, the biological links between the two diseases are poorly characterized. In this review, we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin, a diabetes drug, to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.This publication was made possible by grant #NPRP 5-409-3-112 from the Qatar National Research Fund (a member of Qatar Foundation)

Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From Gprc5a-Deficient Murine Lung Adenocarcinoma With Somatic Kras Mutations

Lung adenocarcinomas (LUADs) with somatic mutations in the KRAS oncogene comprise the most common molecular subtype of lung cancer in smokers and present with overall dismal prognosis and resistance to most therapies. Our group recently demonstrated that tobacco carcinogen-exposed mice with knockout of the airway lineage G-protein coupled receptor, Gprc5a, develop LUADs with somatic mutations in Kras. Earlier work has suggested that cancer stem cells (CSCs) play crucial roles in clonal evolution of tumors and in therapy resistance. To date, our understanding of CSCs in LUADs with somatic Kras mutations remains lagging. Here we derived CSCs (as spheres in 3D cultures) with self-renewal properties from a murine Kras-mutant LUAD cell line we previously established from a tobacco carcinogen-exposed Gprc5a−/− mouse. Using syngeneic Gprc5a−/− models, we found that these CSCs, compared to their parental isoforms, exhibited increased tumorigenic potential in vivo, particularly in female animals. Using whole-transcriptome sequencing coupled with pathways analysis and confirmatory PCR, we identified gene features (n = 2,600) differentially expressed in the CSCs compared to parental cells and that were enriched with functional modules associated with an augmented malignant phenotype including stemness, tumor-promoting inflammation and anti-oxidant responses. Further, based on in silico predicted activation of GSK3β in CSCs, we found that tideglusib, an irreversible inhibitor of the kinase, exhibited marked anti-growth effects in the cultured CSCs. Our study underscores molecular cues in the pathogenesis of Kras-mutant LUAD and presents new models to study the evolution, and thus high-potential targets, of this aggressive malignancy

EMT Markers in Locally-Advanced Prostate Cancer: Predicting Recurrence?

Background: Prostate cancer (PCa) is the second most frequent cause of cancer-related death in men worldwide. It is a heterogeneous disease at molecular and clinical levels which makes its prognosis and treatment outcome hard to predict. The epithelial-to-mesenchymal transition (EMT) marks a key step in the invasion and malignant progression of PCa. We sought to assess the co-expression of epithelial cytokeratin 8 (CK8) and mesenchymal vimentin (Vim) in locally-advanced PCa as indicators of EMT and consequently predictors of the progression status of the disease.Methods: Co-expression of CK8 and Vim was evaluated by immunofluorescence (IF) on paraffin-embedded tissue sections of 122 patients with PCa who underwent radical prostatectomies between 1998 and 2016 at the American University of Beirut Medical Center (AUBMC). EMT score was calculated accordingly and then correlated with the patients' clinicopathological parameters and PSA failure.Results: The co-expression of CK8/Vim (EMT score), was associated with increasing Gleason group. A highly significant linear association was detected wherein higher Gleason group was associated with higher mean EMT score. In addition, the median estimated biochemical recurrence-free survival for patients with < 25% EMT score was almost double that of patients with more than 25%. The validity of this score for prediction of prognosis was further demonstrated using cox regression model. Our data also confirmed that the EMT score can predict PSA failure irrespective of Gleason group, pathological stage, or surgical margins.Conclusion: This study suggests that assessment of molecular markers of EMT, particularly CK8 and Vim, in radical prostatectomy specimens, in addition to conventional clinicopathological prognostic parameters, can aid in the development of a novel system for predicting the prognosis of locally-advanced PCa

How Safe Is Gadobutrol? Examining the Effect of Gadolinium Deposition on the Nervous System

This study aimed to evaluate the safety of gadobutrol, a gadolinium-based contrast agent used in medical imaging, by investigating its effect on the nervous system under physiological and inflammatory conditions. Male Sprague Dawley rats were divided randomly into four groups, including gadobutrol, saline, LPS + gadobutrol, and LPS + saline, and were given intraperitoneal injections of gadobutrol (2.5 mmol/kg) or saline for 20 days. Weekly sensorimotor and cognitive behavioral tests were performed over 4 weeks, and Gd concentration in nervous tissues was analyzed using inductively coupled plasma mass spectrometry (ICP-MS). Lactate dehydrogenase (LDH) activity was measured to evaluate cytotoxicity, and electromyography (EMG) recordings from the gastrocnemius muscle were also obtained to examine signal transmission in sciatic nerves. The results indicated that gadobutrol did not induce significant behavioral changes under normal conditions. However, when administered along with LPS, the combination led to behavioral dysfunction. ICP-MS analysis revealed a higher concentration of Gd in the cerebrum and spinal cord of gadobutrol + LPS-treated rats, while peripheral nerves showed lower concentrations. In addition, there was a significant increase in LDH activity in the hippocampus of the gadobutrol group. EMG responses to electrical stimulation of the sciatic nerve demonstrated a decreased threshold of nociceptive reflexes in the gadobutrol group. Overall, while gadobutrol may be considered safe under normal physiological conditions, the findings suggest that its safety may be compromised under inflammatory conditions