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DNMT3A/miR-129-2-5p/Rac1 Is an Effector Pathway for SNHG1 to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells

Xu, Jiheng; Yang, Rui; Li, Jingxia; Wang, Lidong; Cohen, Mitchell; Simeone, Diane M; Costa, Max; Wu, Xue-Ru
The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that SNHG1, a long non-coding RNA that is over-expressed in ~95% of human muscle-invasive bladder cancers (MIBCs), induces stem-cell-like sphere formation and the invasion of cultured bladder cancer cells by upregulating Rho GTPase, Rac1. We further show that SNHG1 binds to DNA methylation transferase 3A protein (DNMT3A), and tethers DNMT3A to the promoter of miR-129-2, thus hyper-methylating and repressing miR-129-2-5p transcription. The reduced binding of miR-129-2 to the 3'-UTR of Rac1 mRNA leads to the stabilization of Rac1 mRNA and increased levels of Rac1 protein, which then stimulates MIBC cell sphere formation and invasion. Analysis of the Human Protein Atlas shows that a high expression of Rac1 is strongly associated with poor survival in patients with MIBC. Our data strongly suggest that the SNHG1/DNMT3A/miR-129-2-5p/Rac1 effector pathway drives stem-cell-like and invasive behaviors in MIBC, a deadly form of bladder cancer. Targeting this pathway, alone or in combination with platinum-based therapy, may reduce chemoresistance and improve longer-term outcomes in MIBC patients.
PMID: 36077697
ISSN: 2072-6694
CID: 5337182

Longitudinal Impact of WTC Dust Inhalation on Rat Cardiac Tissue Transcriptomic Profiles

Park, Sung-Hyun; Lu, Yuting; Shao, Yongzhao; Prophete, Colette; Horton, Lori; Sisco, Maureen; Lee, Hyun-Wook; Kluz, Thomas; Sun, Hong; Costa, Max; Zelikoff, Judith; Chen, Lung-Chi; Gorr, Matthew W; Wold, Loren E; Cohen, Mitchell D
First responders (FR) exposed to the World Trade Center (WTC) Ground Zero air over the first week after the 9/11 disaster have an increased heart disease incidence compared to unexposed FR and the general population. To test if WTC dusts were causative agents, rats were exposed to WTC dusts (under isoflurane [ISO] anesthesia) 2 h/day on 2 consecutive days; controls received air/ISO or air only. Hearts were collected 1, 30, 240, and 360 d post-exposure, left ventricle total RNA was extracted, and transcription profiles were obtained. The data showed that differentially expressed genes (DEG) for WTC vs. ISO rats did not reach any significance with a false discovery rate (FDR) < 0.05 at days 1, 30, and 240, indicating that the dusts did not impart effects beyond any from ISO. However, at day 360, 14 DEG with a low FDR were identified, reflecting potential long-term effects from WTC dust alone, and the majority of these DEG have been implicated as having an impact on heart functions. Furthermore, the functional gene set enrichment analysis (GSEA) data at day 360 showed that WTC dust could potentially impact the myocardial energy metabolism via PPAR signaling and heart valve development. This is the first study showing that WTC dust could significantly affect some genes that are associated with the heart/CV system, in the long term. Even > 20 years after the 9/11 disaster, this has potentially important implications for those FR exposed repeatedly at Ground Zero over the first week after the buildings collapsed.
PMID: 35055737
ISSN: 1660-4601
CID: 5131772


Chapter by: Cohen, Mitchell D.
in: Handbook on the Toxicology of Metals by
[S.l.] : Elsevier Inc., 2021
pp. 937-961
ISBN: 9780128229460
CID: 5189492

Health effects following exposure to dust from the World Trade Center disaster: An update

Mears, Matthew J; Aslaner, David M; Barson, Chad T; Cohen, Mitchell D; Gorr, Matthew W; Wold, Loren E
Exposure to dust, smoke, and fumes containing volatile chemicals and particulate matter (PM) from the World Trade Center (WTC) towers' collapse impacted thousands of citizens and first responders (FR; firefighters, medicals staff, police officers) of New York City. Surviving FR and recovery workers are increasingly prone to age-related diseases that their prior WTC dust exposures might expedite or make worse. This review provides an overview of published WTC studies concerning FR/recovery workers' exposure and causal mechanisms of age-related disease susceptibility, specifically those involving the cardiopulmonary and neurological systems. This review highlights the recent findings of the major health effects of cardiovascular, pulmonary, and neurological health sequelae from WTC dust exposure. To better treat those that risked their lives during and after the disaster of September 11, 2001, the deleterious mechanisms that WTC dust exposure exerted and continue to exert on the heart, lungs, and brain of FR must be better understood.
PMID: 34785191
ISSN: 1879-0631
CID: 5049122

2021 PACES Expert Consensus Statement on the Indications and Management of Cardiovascular Implantable Electronic Devices in Pediatric Patients

Shah, Maully J; Silka, Michael J; Silva, Jennifer Avari; Balaji, Seshadri; Beach, Cheyenne; Benjamin, Monica; Berul, Charles; Cannon, Bryan; Cecchin, Frank; Cohen, Mitchell; Dalal, Aarti; Dechert, Brynn; Foster, Anne; Gebauer, Roman; Gonzalez Corcia, M Cecilia; Kannankeril, Prince; Karpawich, Peter; Kim, Jeffery; Krishna, Mani Ram; Kubuš, Peter; Malloy-Walton, Lindsey; LaPage, Martin; Mah, Doug; Miyazaki, Aya; Motonaga, Kara; Niu, Mary; Olen, Melissa; Paul, Thomas; Rosenthal, Eric; Saarel, Elizabeth; Silvetti, Massimo Stefano; Stephenson, Elizabeth; Tan, Reina; Triedman, John; Von Bergen, Nicholas; Wackel, Philip
In view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consenus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology, (ACC) and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate follow-up in pediatric patients.
PMID: 34338183
ISSN: 1467-1107
CID: 4979802

Longitudinal impact on rat cardiac tissue transcriptomic profiles due to acute intratracheal inhalation exposures to isoflurane

Park, Sung-Hyun; Lu, Yuting; Shao, Yongzhao; Prophete, Colette; Horton, Lori; Sisco, Maureen; Lee, Hyun-Wook; Kluz, Thomas; Sun, Hong; Costa, Max; Zelikoff, Judith; Chen, Lung-Chi; Cohen, Mitchell D
Isoflurane (ISO) is a widely used inhalation anesthetic in experiments with rodents and humans during surgery. Though ISO has not been reported to impart long-lasting side effects, it is unknown if ISO can influence gene regulation in certain tissues, including the heart. Such changes could have important implications for use of this anesthetic in patients susceptible to heart failure/other cardiac abnormalities. To test if ISO could alter gene regulation/expression in heart tissues, and if such changes were reversible, prolonged, or late onset with time, SHR (spontaneously hypertensive) rats were exposed by intratracheal inhalation to a 97.5% air/2.5% ISO mixture on two consecutive days (2 hr/d). Control rats breathed filtered air only. On Days 1, 30, 240, and 360 post-exposure, rat hearts were collected and total RNA was extracted from the left ventricle for global gene expression analysis. The data revealed differentially-expressed genes (DEG) in response to ISO (compared to naïve control) at all post-exposure timepoints. The data showed acute ISO exposures led to DEG associated with wounding, local immune function, inflammation, and circadian rhythm regulation at Days 1 and 30; these effects dissipated by Day 240. There were other significantly-increased DEG induced by ISO at Day 360; these included changes in expression of genes associated with cell signaling, differentiation, and migration, extracellular matrix organization, cell-substrate adhesion, heart development, and blood pressure regulation. Examination of consistent DEG at Days 240 and 360 indicated late onset DEG reflecting potential long-lasting effects from ISO; these included DEG associated with oxidative phosphorylation, ribosome, angiogenesis, mitochondrial translation elongation, and focal adhesion. Together, the data show acute repeated ISO exposures could impart variable effects on gene expression/regulation in the heart. While some alterations self-resolved, others appeared to be long-lasting or late onset. Whether such changes occur in all rat models or in humans remains to be investigated.
PMID: 34648499
ISSN: 1932-6203
CID: 5046652

lncRNA SNHG1 Promotes Basal Bladder Cancer Invasion via Interaction with PP2A Catalytic Subunit and Induction of Autophagy

Xu, Jiheng; Yang, Rui; Hua, Xiaohui; Huang, Maowen; Tian, Zhongxian; Li, Jingxia; Lam, Hoi Yun; Jiang, Guosong; Cohen, Mitchell; Huang, Chuanshu
Although basal muscle-invasive bladder cancers (MIBCs) are predominant, are more aggressive, and have bad prognoses, molecular mechanisms underlying how basal MIBC formation/progression have been barely explored. In the present study, SNHG1, a long non-coding RNA, was shown to be expressed at higher levels in basal MIBC cells than in other types of bladder BC cells, and its presence could promote basal MIBC cell invasion. The results revealed that SNHG1 specifically induced MMP2 expression via increasing its transcription and mRNA stability. In one mechanism, SNHG1 directly bound with PP2A catalytic subunit (PP2A-c) to inhibit interactions of PP2A-c with c-Jun and then promoted c-Jun phosphorylation that, in turn, mediated MMP2 transcription. In another mechanism, SNHG1 markedly induced autophagy in the cells via induction of increases in the abundance of autophagy-related proteins. The latter initiated autophagy and further abolished miR-34a stability, which reduced overall miR-34a binding directly to the 3' UTR of MMP2 mRNA, thereby promoting MMP2 mRNA stabilization. These results provided novel insight into understanding the specific functions of SNHG1 in basal MIBC. Such findings may ultimately prove highly significant for the design/synthesis of new SNHG1-based compounds for the treatment of basal MIBC patients.
PMID: 32650234
ISSN: 2162-2531
CID: 4517012

Impact on rats from acute intratracheal inhalation exposures to WTC dusts

Cohen, Mitchell D; Prophete, Colette; Horton, Lori; Sisco, Maureen; Park, Sung-Hyun; Lee, Hyun-Wook; Zelikoff, Judith; Chen, Lung-Chi
Background: Studies have revealed the increased incidence of health disorders in First Responders (FR) who were at Ground Zero over the initial 72 hr after the World Trade Center (WTC) collapses. Previous studies in rats exposed to WTC dusts using exposure scenarios that mimicked FR mouthbreathing showed exposure led to altered expression of genes whose products could be involved in lung ailments. Nevertheless, it was uncertain if repeated exposures (as occurred in earliest days post-disaster) might have given rise to long-term changes in the lungs/other organs, in white blood cell (WBC) profiles, and/or systemic expression of select (mostly immune-related) proteins.Methods: To examine this, rats were exposed on 2 consecutive days (2 hr/d, intratracheal inhalation) to WTC dusts and then examined over a 1-yr period thereafter. At select times post-exposure, organ (lung, heart, liver, kidney, spleen) weights, WBC profiles, and blood levels of a variety of proteins were evaluated.Results: The study showed that over the 1-yr period, there were nominal effects on organ weights (absolute, index) as a result of the dust exposures. There were significant changes (relative to in naïve rats) in WBC profiles, with exposed rats having increased monocyte-macrophage and decreased lymphocyte percentages. The study also found that dust exposure led to significant systemic increases in many proteins, including MCP-1, RANTES, MMP-9, RAGE, and Galectin-3.Conclusions: These results provide further support for our longstanding hypothesis that the WTC dusts could potentially have acted as direct inducers of many of the health effects that have been seen in the exposed FR.
PMID: 32448006
ISSN: 1091-7691
CID: 4510282

Overexpressed miR-200a promotes bladder cancer invasion through direct regulating Dicer/miR-16/JNK2/MMP-2 axis

Yang, Rui; Xu, Jiheng; Hua, Xiaohui; Tian, Zhongxian; Xie, Qipeng; Li, Jingxia; Jiang, Guosong; Cohen, Mitchell; Sun, Hong; Huang, Chuanshu
Invasive bladder cancer (BC) is one of the most lethal malignant urological tumors. Although miR-200a has been reported as an onco-miRNA that targets the PTEN gene in endometrioid carcinoma, its biological significance in BC invasion has been poorly explored. In the current study, we found that miR-200a was markedly overexpressed in both human BC tissues and BBN-induced muscle-invasive BC tissues. We further showed that miR-200a overexpression specifically promoted human BC cell invasion, but not migration, via transcriptional upregulation of matrix metalloproteinase (MMP)-2. Mechanistic studies indicated that the increased phosphorylation of c-Jun mediated the increasing levels of MMP-2 mRNA transcription. Further investigation revealed that Dicer was decreased in miR-200a overexpressed BC cells; this resulted in inhibition of miR-16 maturation and consequently led to increased JNK2 protein translation and c-Jun activation. Taken together, the studies here showed that miR-200a overexpression inhibited Dicer expression, in turn, resulted in inhibition of miR-16 maturation, leading to upregulation of JNK2 expression, c-Jun phosphorylation, MMP-2 transcription and, ultimately, BC invasion. Collectively, these results demonstrate that miR-200a is an onco-miRNA that is a positive regulator for BC invasion. This finding could be very useful in the ongoing development of new strategies to treat invasive BC patients.
PMID: 31772330
ISSN: 1476-5594
CID: 4215972

Isorhapontigenin (ISO) inhibits stem cell-like properties and invasion of bladder cancer cell by attenuating CD44 expression

Luo, Yisi; Tian, Zhongxian; Hua, Xiaohui; Huang, Maowen; Xu, Jiheng; Li, Jingxia; Huang, Haishan; Cohen, Mitchell; Huang, Chuanshu
Cancer stem cells (CSC) are highly associated with poor prognosis in cancer patients. Our previous studies report that isorhapontigenin (ISO) down-regulates SOX2-mediated cyclin D1 induction and stem-like cell properties in glioma stem-like cells. The present study revealed that ISO could inhibit stem cell-like phenotypes and invasivity of human bladder cancer (BC) by specific attenuation of expression of CD44 but not SOX-2, at both the protein transcription and degradation levels. On one hand, ISO inhibited cd44 mRNA expression through decreases in Sp1 direct binding to its promoter region-binding site, resulting in attenuation of its transcription. On the other hand, ISO also down-regulated USP28 expression, which in turn reduced CD44 protein stability. Further studies showed that ISO treatment induced miR-4295, which specific bound to 3'-UTR activity of usp28 mRNA and inhibited its translation and expression, while miR-4295 induction was mediated by increased Dicer protein to enhance miR-4295 maturation upon ISO treatment. Our results provide the first evidence that ISO has a profound inhibitory effect on human BC stem cell-like phenotypes and invasivity through the mechanisms distinct from those previously noted in glioma stem-like cells.
PMID: 31222373
ISSN: 1420-9071
CID: 3939392