Dibash Das - Academia.edu (original) (raw)

Papers by Dibash Das

Oncology Times

15 Oncology Times B reast cancer is the second most diagnosed cancer worldwide, with approximatel... more 15 Oncology Times B reast cancer is the second most diagnosed cancer worldwide, with approximately 2.3 million new diagnoses and almost 685,000 breast cancer-related deaths (CA Cancer J Clin 2021; https://doi.org/10.3322/caac.21660). In the United States, approximately 1 in 8 women will develop breast cancer over the course of their lifetime. Finding breast cancer early is one of the most important strategies to prevent deaths from breast cancer. According to the American Cancer Society, when breast cancer is detected early and is in the localized stage, the 5-year relative survival rate is 99 percent. In order to promote the early detection of cancer, the World Health Organization (WHO) has defined two distinct but related strategies: 1) screening, which refers to the tests and exams used to identify asymptomatic disease in a target population of apparently healthy individuals, and 2) early diagnosis, which refers to finding and recognizing symptomatic cancer at an early stage. Studies have shown that lowand middle-income countries bear a growing and lopsided share of the disease burden (Am J Cancer Res 2020;10(5):1568-1591). Country case examples have highlighted the opportunities and obstacles of employing effective breast cancer early detection programs, and the complex interplay of barriers and facilitators to achieving early detection for breast cancer in real-world settings. In all case studies, the indispensable obstacle is the same: the main cause of poor survival is a late-stage diagnosis. In these settings, multifaceted challenges to early detection, such as economic, social, geographic, and other interconnected issues, can hinder a woman’s access to early detection as well as judicious, effective, and affordable care. Efforts to overcome these challenges need to be multipronged to significantly decrease breast cancer mortality globally. In a recent consensus article from the sixth Breast Health Global Initiative Global Summit, “Breast cancer early detection: A phased approach to implementation,” Ophira Ginsburg, MD, and colleagues describe phases of early detection programs in order to ensure that critical components for improving breast cancer outcomes are established in a rational manner (Cancer 2020; https://doi.org/10.1002/ cncr.32887). Essential components of breast cancer early detection programs include recognizing the target population, defining the diagnostic tools, explaining the program strategies, and determining the rollout and scale-up process. Of course, for each element, different alternatives may be implemented, thereby ensuing in varied strategies. The phased implementation approach can be applied sequentially or in parallel, contingent on the specific environment in which implementation is taking place to advance high-quality breast health care. Overall, each phase necessitates continuous assessment and improvement to establish and sustain quality. Addressing any one of these phases in isolation will not improve breast cancer outcomes.

Poster Presentations - Proffered Abstracts

Cancers

Dysregulated activity of helicase eIF4A drives transformation to and maintenance of cancer cell p... more Dysregulated activity of helicase eIF4A drives transformation to and maintenance of cancer cell phenotype by reprogramming cellular translation. Interleukin 24 (IL-24) is a tumor-suppressing protein, which has the ability to inhibit angiogenesis, sensitize cancer cells to chemotherapy, and induce cancer cell-specific apoptosis. In this study, we found that eIF4A is inhibited by IL-24. Consequently, selective reduction of translation was observed for mRNAs harboring strong secondary structures in their 5-untranslated regions (5 UTRs). These mRNAs encode proteins, which function in cell survival and proliferation. Consistently, overexpression of eIF4A conferred cancer cells with resistance to IL-24-induced cell death. It has been established that inhibition of eIF4A triggers mitochondrial-mediated apoptosis. We showed that IL-24 induces eIF4A-dependent mitochondrial depolarization. We also showed that IL-24 induces Sigma 1 Receptor-dependent eIF4A down-regulation and mitochondrial depolarization. Thus, the progress of apoptosis triggered by IL-24 is characterized by a complex program of changes in regulation of several initiation factors, including the eIF4A.

RNA Biology in Cancer (Splicing, Noncoding RNAs, RNA Modifications)

node metastasis in young TNBC patients. Our results showed that NOS3 expression level was recipro... more node metastasis in young TNBC patients. Our results showed that NOS3 expression level was reciprocally up-regulated.On the molecular level, sONE siRNAs resulted in an increase in NOS3 levels and NO production in MDA-MB-231. On the functional level, knocking down of sONE levels resulted in a significant increase of cellular viability and cellular proliferation rates of MDA-MB-231 Conclusion This study highlights a novel prognostic value of sONE in young TNBC patients where sONE expression level was negatively correlated with the aggressiveness of the disease. Moreover, this study validated sONE/NOS3/NO as a novel tumour suppressor signalling axis in BC patients.

Acta Physiologica

Myokines are molecules produced and secreted by skeletal muscle to act in an auto‐, para‐ and end... more Myokines are molecules produced and secreted by skeletal muscle to act in an auto‐, para‐ and endocrine manner to alter physiological function of target tissues. The growing number of effects of myokines on metabolism of distant tissues provides a compelling case for crosstalk between skeletal muscle and other tissues and organs to regulate metabolic homoeostasis. In this review, we summarize and discuss the current knowledge regarding the impact on metabolism of several canonical and recently identified myokines. We focus specifically on myostatin, β‐aminoisobutyric acid, interleukin‐15, meteorin‐like and myonectin, and discuss how these myokines are induced and regulated as well as their overall function. We also review how these myokines may serve as potential prognostic biomarkers that reflect whole‐body metabolism and how they may be attractive therapeutic targets for treating muscle and metabolic diseases.

Journal of Neurotrauma

Spinal cord injury is a devastating, life-altering neurological event that affects approximately ... more Spinal cord injury is a devastating, life-altering neurological event that affects approximately 300,000 individuals in the United States. Currently, there are no effective treatments to reverse the neurological impairments caused by the lesion. Until a cure is available, there is an urgent need for strategies that can either spare injured neurons or promote neuroplasticity and functional recovery. Genetic links to outcomes after SCI may provide insights into the pathological mechanisms, and possible new avenues for drug development. In the present review, we discuss the current knowledge linking apolipoprotein E genotypes with better or worse functional outcomes after a spinal cord injury, and the possible molecular mechanisms that may contribute to this association.

Molecular and Cellular Biology / Genetics

Prostate cancer (PCa) is the second most common cancer and third deadliest cancer in American men... more Prostate cancer (PCa) is the second most common cancer and third deadliest cancer in American men, yet the only established risk factors are familial genetics, age and race. Men of African Ancestry (moAA) have higher PCa incidence rates when compared to Caucasian men in the United States, which are due to differences in genetic susceptibility variants. Moreover, high mortality rates of PCa are associated with castration-resistant prostate cancer (CRPC) due to maintenance of androgen receptor (AR) signaling in PCa cells following androgen ablation therapy. The 8q24 chromosomal locus is a highly susceptible PCa region that has frequent amplifications of the c-MYC oncogene and downstream PVT1 gene. PVT1 is a long non-protein coding gene that encodes six annotated microRNAs (miRNAs), including microRNA-1205 (miR-1205), yet the function of these miRNAs are poorly understood. To elucidate the role of miR-1205 in PCa, we examined miR-1205 mRNA expression in a cohort of normal (n=22), benign (n=42), and malignant (n=26) histologically confirmed prostatic tissues obtained from prostatectomy or transrectal biopsies of moAA men in Ibadan, Nigeria. One-way ANOVA analysis determined changes in the relative expression of miR-1205 between groups (F(2,87) = 1.153) and a Tukey post hoc test revealed decreased miR-1205 expression in benign (4.61 ± 7.5) and malignant tumors (3.39 ± 3.53) when compared to normal tissues (6.55 ± 9.5). These data suggest that miR-1205 may function as a miRNA tumor suppressor and is characteristic to moAA-associated PCa. To elucidate the molecular mechanism of miR-1205, we examined AR and c-MYC mRNA expression using androgen-dependent LNCaP and CRPC C4-2B and 22RV1 cells. We observed a two-fold decrease of miR-1205 expression and overexpression of AR and c-MYC in C4-2B and 22RV1 cells when compared to LNCaP, suggesting that miR-1205 may regulate AR and c-MYC signaling in CRPC. Next, we identified Fry-like (FRYL) as a putative target using a miSVR computer algorithm and subsequently performed whole transcriptome analysis on prostate tumors and adjacent normal tissue from fourteen PCa patients using the Galaxy web platform. FRYL and AR overexpression was observed in diseased patients suggesting that FRYL may function as an oncogene. Moreover, FRYL was overexpressed in C4-2B and 22RV1 cells when compared to LNCaP, further suggesting a role in CRPC development. C4-2B cells transfected with miR-1205 and the 39UTR of FRYL in a luciferase expressing vector revealed a significant decrease in luciferase activity when compared to control cells, indicating direct binding of miR-1205 to the 39UTR of FRYL. These observations strongly suggest that miR-1205 acts as a tumor suppressor that may regulate AR and c-MYC expression, and directly targets the 39UTR of FRYL in PCa cells. Further understanding the role of miR-1205 regulation of FRYL, AR, and c-MYC signaling may provide novel insights into the molecular mechanisms of CRPC. Citation Format: Michelle K. Naidoo, Dibash K. Das, Adeodat Ilboudo, Akintunde Orunmuyi, Gabriel O. Ogun, S. A. Adebayo, E. O. Olapade-Olaopa, Olorunseun Ogunwobi. MicroRNA-1205 as a tumor suppressor in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 503.

Cell, Molecular, and Tumor Biology

Prostate cancer is the 2nd most common cancer in the world for men. For reasons still unclear, ag... more Prostate cancer is the 2nd most common cancer in the world for men. For reasons still unclear, aggressive PCa disproportionately affects males of African ancestry (MoAA). Incidence and mortality rates are highest in MoAA as they have consistently shown a 2.3-3.0-fold higher risk of mortality compared to Caucasian men (CM). This aggressiveness of PCa may be due to specific biologic factors. Located downstream of c-Myc at chromosome 8q24 is PVT1, which encodes miR-1207-3p. Studies have shown that PVT1/MYC cooperation is a fundamental feature in all cancers with 8q24 amplification, and 98% of the 8q24 amplicons contained concurrent amplification of the MYC and PVT1 loci. Moreover, MYC has been linked to PCa aggressiveness and has been reported to be downstream of AR in some PCa. However, the mechanisms regulating c-MYC have never been studied in MoAA. We recently demonstrated that miR-1207-3p directly binds to FNDC1 to regulate a novel FNDC1/FN1/AR pathway upregulated in metastatic prostate cancer (PCa). However, the mechanisms regulating c-Myc in PCa remain unclear, and the relevance of our novel and clinically significant miR-1207-3p molecular pathway in PCa in MoAA is unknown. The aim of this study was to determine if c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. We used qPCR, immunoblotting, RNA pulldown, proliferation, migration, and apoptosis assays to evaluate miR-1207-3p regulation of c-Myc in aggressive PCa in MoAA. Also, miR-1207-3p, FNDC1, FN1, AR, and c-Myc expression was analyzed in prostate tissues (normal = 21; benign = 41; tumor = 26) of patients who received prostatectomy or transrectal ultrasound-guided biopsies at the University College Hospital, Ibadan, Nigeria, a sub-Saharan Black African population. Seventeen patients had tumor tissues with Gleason score ≥ 8. Tissues were collected in compliance with Institutional Review Board-approved protocols. ANOVA, student9s t-test, and Tukey post-hoc tests were used for statistical analysis. Prostate tissue analysis revealed that underexpression of miR-1207-3p and the overexpression of FNDC1, FN1, AR, and c-Myc is significantly associated with aggressive PCa in MoAA. Also, miR-1207-3p was underexpressed while FNDC1 and c-MYC were overexpressed in tumors with Gleason score ≥8 in comparison to those with Gleason score 75% in the MoAA-derived indolent E006AA PCa cell line and the MoAA-derived aggressive/castration-resistant E006AA-hT PCa cell line, indicating that c-Myc is downstream of AR. c-Myc expression is higher in the E006AA-hT PCa cell line when compared to the E006AA PCa cell line, suggesting that c-Myc is associated with aggressive PCa. Moreover, NB1207 significantly inhibited migration and induced apoptosis in E006AA and E006AA-hT PCa cell lines. Next, we compared the efficacy of NB1207 in inhibiting proliferation to the commercially available drugs for treatment of CPRC (enzalutamide and abiraterone). NB1207 inhibited proliferation in the CRPC cell line E006AA-hT by nearly 50% while enzalutamide and abiraterone had no effect. In conclusion, miR-1207-3p regulates c-Myc expression via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. miR-1207-3p may be a biomarker for risk stratification in PCa in MoAA. NB1207 has potential for therapeutic targeting of c-Myc for treatment of aggressive PCa in MoAA. Citation Format: Dibash K. Das, Akintunde T. Orunmuyi, Gabriel Olabiyi Ogun, S. Adekola Adebayo, A. Ayo Salako, Adeodat Ilboudo, Cuong Bach, E. O. Olapade-Olaopa, Olorunseun O. Ogunwobi. c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B61.

Non-Coding RNA

Prostate cancer (PCa) is the second leading cause of cancer death in the United States. The five-... more Prostate cancer (PCa) is the second leading cause of cancer death in the United States. The five-year survival rate for men diagnosed with localized PCa is nearly 100%, yet for those diagnosed with aggressive PCa, it is less than 30%. The pleiotropic cytokine Interleukin-24 (IL-24) has been shown to specifically kill PCa cells compared to normal cells when overexpressed in both in vitro and in vivo studies. Despite this, the mechanisms regulating IL-24 in PCa are not well understood. Since specific microRNAs (miRNAs) are dysregulated in PCa, we used miRNA target prediction algorithm tools to identify miR-4719 and miR-6556-5p as putative regulators of IL-24. This study elucidates the expression profile and role of miR-4719 and miR-6756-5p as regulators of IL-24 in PCa. qRT-PCR analysis shows miR-4719 and miR-6756-5p overexpression significantly decreases the expression of IL-24 in PCa cells compared to the negative control. Compared to the indolent PCa and normal prostate epithelial ...

Cancers

The translation of mRNAs plays a critical role in the regulation of gene expression and therefore... more The translation of mRNAs plays a critical role in the regulation of gene expression and therefore, in the regulation of cell proliferation, differentiation and apoptosis. Unrestricted initiation of translation causes malignant transformation and plays a key role in the maintenance and progression of cancers. Translation initiation is regulated by the ternary complex and the eukaryotic initiation factor 4F (eIF4F) complex. The p53 tumor suppressor protein is the most well studied mammalian transcription factor that mediates a variety of anti-proliferative processes. Post-transcriptional mechanisms of gene expression in general and those of translation in particular play a major role in shaping the protein composition of the cell. The p53 protein regulates transcription and controls eIF4F, the ternary complex and the synthesis of ribosomal components, including the down-regulation of rRNA genes. In summary, the induction of p53 regulates protein synthesis and translational control to inhibit cell growth.

International Journal of Molecular Sciences

Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces ca... more Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2α phosphorylation and activating transcription factor 4 (ATF4) action. Our studies show for the first time that cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation is required for IL-24-induced cell death in a variety of breast cancer cell lines and this event increases ATF4 activity. We demonstrate an undocumented role for PKA in regulating IL-24-induced cell death, whereby PKA stimulates phosphorylation of p38 mitogen-activated protein kinase and upregulates extrinsic a...

Cancer Epidemiology Biomarkers & Prevention, 2017

Prostate cancer (PCa) is the most common non-skin cancer and the second leading cause of cancer-r... more Prostate cancer (PCa) is the most common non-skin cancer and the second leading cause of cancer-related death for men in the U.S. Males of African Ancestry (MoAA) have a higher incidence of PCa, compared to Caucasian males (CM). In fact, African ancestry is a confirmed, non-modifiable risk factor for PCa with a 2.5 fold greater risk of lethal PCa in MoAA compared to CM. Discovery of biomarkers with diagnostic, prognostic, and therapeutic applications are necessary to address this profound health disparity. The chromosomal region 8q24 is associated with aggressive PCa in MoAA and variants of this region have been identified to interact with the PVT1 non-coding gene in PCa. PVT1 is located at 8q24 and is transcribed into a long non-coding RNA that has been implicated in PCa. In previous work where we identified at least 12 exons of PVT1, we observed that exon 9 of PVT1 is significantly upregulated in aggressive PCa cell lines derived from MoAA and that silencing expression of PVT1 exon 9 induces apoptosis and cell cycle arrest in aggressive PCa cells derived from MoAA. PVT1 also encodes six annotated microRNAs and we have reported that one of them, miR-1207-3p, has prognostic value in PCa, is differentially expressed in the prostate tumor tissues of MoAA versus CM, and directly binds to the 39 UTR of Fibronectin type III domain containing 1 (FNDC1) to regulate a novel FNDC1/fibronectin (FN1)/androgen receptor (AR) pathway upregulated in metastatic PCa. To further identify racially differentiated cancer-risk factors in the PVT1 locus, we scanned for signatures of population differentiation and positive natural selection using the latest (Release GRCh38) full-genome variability panel from the 1000 Genomes Project. A string of 75 single-nucleotide polymorphisms (SNPs) in a 26-kb region spanning PVT1 exons 4A and 4B consistently show the highest level of genetic differentiation (Fst ~ 0.25) between the African and non-African populations. Nucleotide sequences in the 26-kb region fall into two major phylogenetic clades, including a clade present in all human populations (“Cosmopolitan Clade”), and another clade present nearly exclusively in non-African populations. To investigate the biological functions of the 26-kb element and its potential role in cancer, we examined the expression of PVT1 exons 4A and 4B in a panel of eight PCa cell lines modeling various clinical characteristics, and found that PVT1 exons 4A and 4B are overexpressed in PCa cell lines derived from aggressive PCa in MoAA. Functional studies upon silencing of PVT1 exons 4A and 4B showed an inhibition of cell proliferation when PVT1 exon 4B was silenced in aggressive PCa cells derived from MoAA. To discover all the molecular targets of miR-1207-3p, we designed and synthesized a novel synthetic biotinylated miR-1207-3p duplex and a novel synthetic biotinylated scramble duplex as control, and then we proceeded to validate these novel tools. Our data show that the novel synthetic biotinylated miR-1207-3p duplex directly binds to the 39 UTR of FNDC1 and inhibits the FNDC1/FN1/AR pathway. Wound healing assays revealed that our synthetic biotinylated miR-1207-3p duplex significantly inhibits cellular migration in PCa cells derived from MoAA by up to 40% when compared with the scramble duplex. Furthermore, Annexin V staining analysis demonstrated that our synthetic biotinylated miR-1207-3p duplex increased apoptosis by nearly 2-fold in PCa cells derived from MoAA compared to scramble duplex. These results show that our synthetic biotinylated miR-1207-3p duplex significantly inhibits migration and induces apoptosis. These data demonstrate the importance of PVT1-derived non-coding RNAs in PCa in MoAA, and provide the basis for larger studies to evaluate prognostic, diagnostic, and therapeutic applications of miR-1207-3p, PVT1 exon 9, PVT1 exon 4A and PVT1 exon 4B in PCa. Note: This abstract was not presented at the conference. Citation Format: Adeodat Ilboudo, Dibash Das, Michelle Naidoo, Lia Di, Weigang Qiu, Olorunseun Ogunwobi. PVT1-derived non-coding RNAs in prostate cancer in men of African ancestry. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B14.

Oncology Times

15 Oncology Times B reast cancer is the second most diagnosed cancer worldwide, with approximatel... more 15 Oncology Times B reast cancer is the second most diagnosed cancer worldwide, with approximately 2.3 million new diagnoses and almost 685,000 breast cancer-related deaths (CA Cancer J Clin 2021; https://doi.org/10.3322/caac.21660). In the United States, approximately 1 in 8 women will develop breast cancer over the course of their lifetime. Finding breast cancer early is one of the most important strategies to prevent deaths from breast cancer. According to the American Cancer Society, when breast cancer is detected early and is in the localized stage, the 5-year relative survival rate is 99 percent. In order to promote the early detection of cancer, the World Health Organization (WHO) has defined two distinct but related strategies: 1) screening, which refers to the tests and exams used to identify asymptomatic disease in a target population of apparently healthy individuals, and 2) early diagnosis, which refers to finding and recognizing symptomatic cancer at an early stage. Studies have shown that lowand middle-income countries bear a growing and lopsided share of the disease burden (Am J Cancer Res 2020;10(5):1568-1591). Country case examples have highlighted the opportunities and obstacles of employing effective breast cancer early detection programs, and the complex interplay of barriers and facilitators to achieving early detection for breast cancer in real-world settings. In all case studies, the indispensable obstacle is the same: the main cause of poor survival is a late-stage diagnosis. In these settings, multifaceted challenges to early detection, such as economic, social, geographic, and other interconnected issues, can hinder a woman’s access to early detection as well as judicious, effective, and affordable care. Efforts to overcome these challenges need to be multipronged to significantly decrease breast cancer mortality globally. In a recent consensus article from the sixth Breast Health Global Initiative Global Summit, “Breast cancer early detection: A phased approach to implementation,” Ophira Ginsburg, MD, and colleagues describe phases of early detection programs in order to ensure that critical components for improving breast cancer outcomes are established in a rational manner (Cancer 2020; https://doi.org/10.1002/ cncr.32887). Essential components of breast cancer early detection programs include recognizing the target population, defining the diagnostic tools, explaining the program strategies, and determining the rollout and scale-up process. Of course, for each element, different alternatives may be implemented, thereby ensuing in varied strategies. The phased implementation approach can be applied sequentially or in parallel, contingent on the specific environment in which implementation is taking place to advance high-quality breast health care. Overall, each phase necessitates continuous assessment and improvement to establish and sustain quality. Addressing any one of these phases in isolation will not improve breast cancer outcomes.

Poster Presentations - Proffered Abstracts

Cancers

Dysregulated activity of helicase eIF4A drives transformation to and maintenance of cancer cell p... more Dysregulated activity of helicase eIF4A drives transformation to and maintenance of cancer cell phenotype by reprogramming cellular translation. Interleukin 24 (IL-24) is a tumor-suppressing protein, which has the ability to inhibit angiogenesis, sensitize cancer cells to chemotherapy, and induce cancer cell-specific apoptosis. In this study, we found that eIF4A is inhibited by IL-24. Consequently, selective reduction of translation was observed for mRNAs harboring strong secondary structures in their 5-untranslated regions (5 UTRs). These mRNAs encode proteins, which function in cell survival and proliferation. Consistently, overexpression of eIF4A conferred cancer cells with resistance to IL-24-induced cell death. It has been established that inhibition of eIF4A triggers mitochondrial-mediated apoptosis. We showed that IL-24 induces eIF4A-dependent mitochondrial depolarization. We also showed that IL-24 induces Sigma 1 Receptor-dependent eIF4A down-regulation and mitochondrial depolarization. Thus, the progress of apoptosis triggered by IL-24 is characterized by a complex program of changes in regulation of several initiation factors, including the eIF4A.

RNA Biology in Cancer (Splicing, Noncoding RNAs, RNA Modifications)

node metastasis in young TNBC patients. Our results showed that NOS3 expression level was recipro... more node metastasis in young TNBC patients. Our results showed that NOS3 expression level was reciprocally up-regulated.On the molecular level, sONE siRNAs resulted in an increase in NOS3 levels and NO production in MDA-MB-231. On the functional level, knocking down of sONE levels resulted in a significant increase of cellular viability and cellular proliferation rates of MDA-MB-231 Conclusion This study highlights a novel prognostic value of sONE in young TNBC patients where sONE expression level was negatively correlated with the aggressiveness of the disease. Moreover, this study validated sONE/NOS3/NO as a novel tumour suppressor signalling axis in BC patients.

Acta Physiologica

Myokines are molecules produced and secreted by skeletal muscle to act in an auto‐, para‐ and end... more Myokines are molecules produced and secreted by skeletal muscle to act in an auto‐, para‐ and endocrine manner to alter physiological function of target tissues. The growing number of effects of myokines on metabolism of distant tissues provides a compelling case for crosstalk between skeletal muscle and other tissues and organs to regulate metabolic homoeostasis. In this review, we summarize and discuss the current knowledge regarding the impact on metabolism of several canonical and recently identified myokines. We focus specifically on myostatin, β‐aminoisobutyric acid, interleukin‐15, meteorin‐like and myonectin, and discuss how these myokines are induced and regulated as well as their overall function. We also review how these myokines may serve as potential prognostic biomarkers that reflect whole‐body metabolism and how they may be attractive therapeutic targets for treating muscle and metabolic diseases.

Journal of Neurotrauma

Spinal cord injury is a devastating, life-altering neurological event that affects approximately ... more Spinal cord injury is a devastating, life-altering neurological event that affects approximately 300,000 individuals in the United States. Currently, there are no effective treatments to reverse the neurological impairments caused by the lesion. Until a cure is available, there is an urgent need for strategies that can either spare injured neurons or promote neuroplasticity and functional recovery. Genetic links to outcomes after SCI may provide insights into the pathological mechanisms, and possible new avenues for drug development. In the present review, we discuss the current knowledge linking apolipoprotein E genotypes with better or worse functional outcomes after a spinal cord injury, and the possible molecular mechanisms that may contribute to this association.

Molecular and Cellular Biology / Genetics

Prostate cancer (PCa) is the second most common cancer and third deadliest cancer in American men... more Prostate cancer (PCa) is the second most common cancer and third deadliest cancer in American men, yet the only established risk factors are familial genetics, age and race. Men of African Ancestry (moAA) have higher PCa incidence rates when compared to Caucasian men in the United States, which are due to differences in genetic susceptibility variants. Moreover, high mortality rates of PCa are associated with castration-resistant prostate cancer (CRPC) due to maintenance of androgen receptor (AR) signaling in PCa cells following androgen ablation therapy. The 8q24 chromosomal locus is a highly susceptible PCa region that has frequent amplifications of the c-MYC oncogene and downstream PVT1 gene. PVT1 is a long non-protein coding gene that encodes six annotated microRNAs (miRNAs), including microRNA-1205 (miR-1205), yet the function of these miRNAs are poorly understood. To elucidate the role of miR-1205 in PCa, we examined miR-1205 mRNA expression in a cohort of normal (n=22), benign (n=42), and malignant (n=26) histologically confirmed prostatic tissues obtained from prostatectomy or transrectal biopsies of moAA men in Ibadan, Nigeria. One-way ANOVA analysis determined changes in the relative expression of miR-1205 between groups (F(2,87) = 1.153) and a Tukey post hoc test revealed decreased miR-1205 expression in benign (4.61 ± 7.5) and malignant tumors (3.39 ± 3.53) when compared to normal tissues (6.55 ± 9.5). These data suggest that miR-1205 may function as a miRNA tumor suppressor and is characteristic to moAA-associated PCa. To elucidate the molecular mechanism of miR-1205, we examined AR and c-MYC mRNA expression using androgen-dependent LNCaP and CRPC C4-2B and 22RV1 cells. We observed a two-fold decrease of miR-1205 expression and overexpression of AR and c-MYC in C4-2B and 22RV1 cells when compared to LNCaP, suggesting that miR-1205 may regulate AR and c-MYC signaling in CRPC. Next, we identified Fry-like (FRYL) as a putative target using a miSVR computer algorithm and subsequently performed whole transcriptome analysis on prostate tumors and adjacent normal tissue from fourteen PCa patients using the Galaxy web platform. FRYL and AR overexpression was observed in diseased patients suggesting that FRYL may function as an oncogene. Moreover, FRYL was overexpressed in C4-2B and 22RV1 cells when compared to LNCaP, further suggesting a role in CRPC development. C4-2B cells transfected with miR-1205 and the 39UTR of FRYL in a luciferase expressing vector revealed a significant decrease in luciferase activity when compared to control cells, indicating direct binding of miR-1205 to the 39UTR of FRYL. These observations strongly suggest that miR-1205 acts as a tumor suppressor that may regulate AR and c-MYC expression, and directly targets the 39UTR of FRYL in PCa cells. Further understanding the role of miR-1205 regulation of FRYL, AR, and c-MYC signaling may provide novel insights into the molecular mechanisms of CRPC. Citation Format: Michelle K. Naidoo, Dibash K. Das, Adeodat Ilboudo, Akintunde Orunmuyi, Gabriel O. Ogun, S. A. Adebayo, E. O. Olapade-Olaopa, Olorunseun Ogunwobi. MicroRNA-1205 as a tumor suppressor in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 503.

Cell, Molecular, and Tumor Biology

Prostate cancer is the 2nd most common cancer in the world for men. For reasons still unclear, ag... more Prostate cancer is the 2nd most common cancer in the world for men. For reasons still unclear, aggressive PCa disproportionately affects males of African ancestry (MoAA). Incidence and mortality rates are highest in MoAA as they have consistently shown a 2.3-3.0-fold higher risk of mortality compared to Caucasian men (CM). This aggressiveness of PCa may be due to specific biologic factors. Located downstream of c-Myc at chromosome 8q24 is PVT1, which encodes miR-1207-3p. Studies have shown that PVT1/MYC cooperation is a fundamental feature in all cancers with 8q24 amplification, and 98% of the 8q24 amplicons contained concurrent amplification of the MYC and PVT1 loci. Moreover, MYC has been linked to PCa aggressiveness and has been reported to be downstream of AR in some PCa. However, the mechanisms regulating c-MYC have never been studied in MoAA. We recently demonstrated that miR-1207-3p directly binds to FNDC1 to regulate a novel FNDC1/FN1/AR pathway upregulated in metastatic prostate cancer (PCa). However, the mechanisms regulating c-Myc in PCa remain unclear, and the relevance of our novel and clinically significant miR-1207-3p molecular pathway in PCa in MoAA is unknown. The aim of this study was to determine if c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. We used qPCR, immunoblotting, RNA pulldown, proliferation, migration, and apoptosis assays to evaluate miR-1207-3p regulation of c-Myc in aggressive PCa in MoAA. Also, miR-1207-3p, FNDC1, FN1, AR, and c-Myc expression was analyzed in prostate tissues (normal = 21; benign = 41; tumor = 26) of patients who received prostatectomy or transrectal ultrasound-guided biopsies at the University College Hospital, Ibadan, Nigeria, a sub-Saharan Black African population. Seventeen patients had tumor tissues with Gleason score ≥ 8. Tissues were collected in compliance with Institutional Review Board-approved protocols. ANOVA, student9s t-test, and Tukey post-hoc tests were used for statistical analysis. Prostate tissue analysis revealed that underexpression of miR-1207-3p and the overexpression of FNDC1, FN1, AR, and c-Myc is significantly associated with aggressive PCa in MoAA. Also, miR-1207-3p was underexpressed while FNDC1 and c-MYC were overexpressed in tumors with Gleason score ≥8 in comparison to those with Gleason score 75% in the MoAA-derived indolent E006AA PCa cell line and the MoAA-derived aggressive/castration-resistant E006AA-hT PCa cell line, indicating that c-Myc is downstream of AR. c-Myc expression is higher in the E006AA-hT PCa cell line when compared to the E006AA PCa cell line, suggesting that c-Myc is associated with aggressive PCa. Moreover, NB1207 significantly inhibited migration and induced apoptosis in E006AA and E006AA-hT PCa cell lines. Next, we compared the efficacy of NB1207 in inhibiting proliferation to the commercially available drugs for treatment of CPRC (enzalutamide and abiraterone). NB1207 inhibited proliferation in the CRPC cell line E006AA-hT by nearly 50% while enzalutamide and abiraterone had no effect. In conclusion, miR-1207-3p regulates c-Myc expression via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. miR-1207-3p may be a biomarker for risk stratification in PCa in MoAA. NB1207 has potential for therapeutic targeting of c-Myc for treatment of aggressive PCa in MoAA. Citation Format: Dibash K. Das, Akintunde T. Orunmuyi, Gabriel Olabiyi Ogun, S. Adekola Adebayo, A. Ayo Salako, Adeodat Ilboudo, Cuong Bach, E. O. Olapade-Olaopa, Olorunseun O. Ogunwobi. c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B61.

Non-Coding RNA

Prostate cancer (PCa) is the second leading cause of cancer death in the United States. The five-... more Prostate cancer (PCa) is the second leading cause of cancer death in the United States. The five-year survival rate for men diagnosed with localized PCa is nearly 100%, yet for those diagnosed with aggressive PCa, it is less than 30%. The pleiotropic cytokine Interleukin-24 (IL-24) has been shown to specifically kill PCa cells compared to normal cells when overexpressed in both in vitro and in vivo studies. Despite this, the mechanisms regulating IL-24 in PCa are not well understood. Since specific microRNAs (miRNAs) are dysregulated in PCa, we used miRNA target prediction algorithm tools to identify miR-4719 and miR-6556-5p as putative regulators of IL-24. This study elucidates the expression profile and role of miR-4719 and miR-6756-5p as regulators of IL-24 in PCa. qRT-PCR analysis shows miR-4719 and miR-6756-5p overexpression significantly decreases the expression of IL-24 in PCa cells compared to the negative control. Compared to the indolent PCa and normal prostate epithelial ...

Cancers

The translation of mRNAs plays a critical role in the regulation of gene expression and therefore... more The translation of mRNAs plays a critical role in the regulation of gene expression and therefore, in the regulation of cell proliferation, differentiation and apoptosis. Unrestricted initiation of translation causes malignant transformation and plays a key role in the maintenance and progression of cancers. Translation initiation is regulated by the ternary complex and the eukaryotic initiation factor 4F (eIF4F) complex. The p53 tumor suppressor protein is the most well studied mammalian transcription factor that mediates a variety of anti-proliferative processes. Post-transcriptional mechanisms of gene expression in general and those of translation in particular play a major role in shaping the protein composition of the cell. The p53 protein regulates transcription and controls eIF4F, the ternary complex and the synthesis of ribosomal components, including the down-regulation of rRNA genes. In summary, the induction of p53 regulates protein synthesis and translational control to inhibit cell growth.

International Journal of Molecular Sciences

Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces ca... more Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2α phosphorylation and activating transcription factor 4 (ATF4) action. Our studies show for the first time that cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation is required for IL-24-induced cell death in a variety of breast cancer cell lines and this event increases ATF4 activity. We demonstrate an undocumented role for PKA in regulating IL-24-induced cell death, whereby PKA stimulates phosphorylation of p38 mitogen-activated protein kinase and upregulates extrinsic a...

Cancer Epidemiology Biomarkers & Prevention, 2017

Prostate cancer (PCa) is the most common non-skin cancer and the second leading cause of cancer-r... more Prostate cancer (PCa) is the most common non-skin cancer and the second leading cause of cancer-related death for men in the U.S. Males of African Ancestry (MoAA) have a higher incidence of PCa, compared to Caucasian males (CM). In fact, African ancestry is a confirmed, non-modifiable risk factor for PCa with a 2.5 fold greater risk of lethal PCa in MoAA compared to CM. Discovery of biomarkers with diagnostic, prognostic, and therapeutic applications are necessary to address this profound health disparity. The chromosomal region 8q24 is associated with aggressive PCa in MoAA and variants of this region have been identified to interact with the PVT1 non-coding gene in PCa. PVT1 is located at 8q24 and is transcribed into a long non-coding RNA that has been implicated in PCa. In previous work where we identified at least 12 exons of PVT1, we observed that exon 9 of PVT1 is significantly upregulated in aggressive PCa cell lines derived from MoAA and that silencing expression of PVT1 exon 9 induces apoptosis and cell cycle arrest in aggressive PCa cells derived from MoAA. PVT1 also encodes six annotated microRNAs and we have reported that one of them, miR-1207-3p, has prognostic value in PCa, is differentially expressed in the prostate tumor tissues of MoAA versus CM, and directly binds to the 39 UTR of Fibronectin type III domain containing 1 (FNDC1) to regulate a novel FNDC1/fibronectin (FN1)/androgen receptor (AR) pathway upregulated in metastatic PCa. To further identify racially differentiated cancer-risk factors in the PVT1 locus, we scanned for signatures of population differentiation and positive natural selection using the latest (Release GRCh38) full-genome variability panel from the 1000 Genomes Project. A string of 75 single-nucleotide polymorphisms (SNPs) in a 26-kb region spanning PVT1 exons 4A and 4B consistently show the highest level of genetic differentiation (Fst ~ 0.25) between the African and non-African populations. Nucleotide sequences in the 26-kb region fall into two major phylogenetic clades, including a clade present in all human populations (“Cosmopolitan Clade”), and another clade present nearly exclusively in non-African populations. To investigate the biological functions of the 26-kb element and its potential role in cancer, we examined the expression of PVT1 exons 4A and 4B in a panel of eight PCa cell lines modeling various clinical characteristics, and found that PVT1 exons 4A and 4B are overexpressed in PCa cell lines derived from aggressive PCa in MoAA. Functional studies upon silencing of PVT1 exons 4A and 4B showed an inhibition of cell proliferation when PVT1 exon 4B was silenced in aggressive PCa cells derived from MoAA. To discover all the molecular targets of miR-1207-3p, we designed and synthesized a novel synthetic biotinylated miR-1207-3p duplex and a novel synthetic biotinylated scramble duplex as control, and then we proceeded to validate these novel tools. Our data show that the novel synthetic biotinylated miR-1207-3p duplex directly binds to the 39 UTR of FNDC1 and inhibits the FNDC1/FN1/AR pathway. Wound healing assays revealed that our synthetic biotinylated miR-1207-3p duplex significantly inhibits cellular migration in PCa cells derived from MoAA by up to 40% when compared with the scramble duplex. Furthermore, Annexin V staining analysis demonstrated that our synthetic biotinylated miR-1207-3p duplex increased apoptosis by nearly 2-fold in PCa cells derived from MoAA compared to scramble duplex. These results show that our synthetic biotinylated miR-1207-3p duplex significantly inhibits migration and induces apoptosis. These data demonstrate the importance of PVT1-derived non-coding RNAs in PCa in MoAA, and provide the basis for larger studies to evaluate prognostic, diagnostic, and therapeutic applications of miR-1207-3p, PVT1 exon 9, PVT1 exon 4A and PVT1 exon 4B in PCa. Note: This abstract was not presented at the conference. Citation Format: Adeodat Ilboudo, Dibash Das, Michelle Naidoo, Lia Di, Weigang Qiu, Olorunseun Ogunwobi. PVT1-derived non-coding RNAs in prostate cancer in men of African ancestry. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B14.