Elucidating the molecular signaling of Cadmium Carcinogenesis

阐明镉致癌的分子信号传导

• 批准号: 10338822
• 负责人: Chendil Damodaran
• 金额: $ 51.07万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-02 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338822
• 关键词: Anatomy; Apoptotic; Benign Prostatic Hypertrophy; Binding; Blood; CRISPR/Cas technology; Cadmium; Carcinogens; Carcinoma; Cells; Cerebellum; Chronic; Clinical; Development; Dose; Epidemiology; Exposure to; Family; GLI gene; Glioma; Goals; Health; Human; In Vitro; Knockout Mice; Knowledge; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metals; Modeling; Molecular; Mus; Oncogenes; Oncogenic; Patients; Pattern; Peripheral; Pharmacology; Plasma; Prostate; Proteins; Regulation; Response Elements; Risk; Risk Factors; Role; SHH gene; Serum; Signal Transduction; Specimen; Squamous cell carcinoma; Tamoxifen; Tissues; Tumor Tissue; Urine; Xenograft procedure; Zinc Fingers; base; carcinogenesis; cohort; exposed human population; genetic approach; in vivo; innovation; insight; molecular marker; mouse model; overexpression; pre-clinical; smoothened signaling pathway; subcutaneous; tool; transcription factor; tumor; tumorigenesis

Project Summary/Abstract Cadmium (Cd) is a known human carcinogen and risk factor for prostate cancer (CaP). The human prostate is composed of three anatomic zones, namely the peripheral zone (PZ), transition zone (TZ), and central zone (CZ). CaP arises primarily in the PZ of the prostate and followed by the TZ. Our in vivo studies suggest that Cd-exposure induced different types of prostate malignances such as, Squamous cell carcinoma (SCC) in TZ and poorly differentiated carcinoma (PDC) in PZ of the prostate. Hence, the goal of the study is to understand the pathobiology and the molecular landscape of Cd-induced SCC in laboratory models (in vitro and in vivo) and clinical specimens. Chronic exposure of plasma concentrations of Cd in TZ of prostate cells formed tumors (SCC) in xenotransplanted mice that differed from Cd-induced tumors (PDC) in the PZ of the prostate. Subsequent, analysis of the mechanism of action revealed that Cd exposure induced the expression of zinc- finger of the cerebellum 2 (ZIC2) in the benign prostate hyperplasia (BPH: TZ) cells but not in RWPE-1 (PZ) cells. At a molecular level, ZIC2 interacts with glioma-associated oncogene family zinc finger 1 (GLI1), a downstream target of sonic hedgehog (Shh) signaling, which activates the pro-survival machinery in Cd- exposed BPH1 cells. Similarly, overexpression of ZIC2 in RWPE-1 cells resulted in spheroid formation, confirming the oncogenic function of ZIC2. Also, we found ZIC2, and GLI1 expressions were correspondingly increased in different grades of CaP as compared to BPH or adjacent healthy tissue (Chandrasekaran et al.,2020 Oncogenesis). Based on these results, we hypothesize that the activation of ZIC2 and GLI1 is responsible for the malignant transformation (SCC) of Cd exposed BPH cells. Aim 1: Dissect the mechanism by which Cd activates ZIC2 and determine whether ZIC2 activation is essential for the malignant transformation of BPH1 & BPH/hTERT1 cells. Aim-2: Determine the molecular interplay between ZIC2 and GLI1 activation and examine their function in Cd exposed BPH1 & BPH/hTERT1 cells. Aim 3: Study Cd- induced tumorigenesis in mouse models and validate molecular markers in human CaP specimens. The successful completion of the studies will not only contribute new information towards filling the lacunae of knowledge regarding the pathobiology of Cd-induced SCC, but also provide an insight into the molecular mechanisms (MTF-1, ZIC2 and GLI1 signaling) pertaining to SCC as well as other metal induced malignances.

项目总结/摘要 镉（Cd）是一种已知的人类致癌物和前列腺癌（CaP）的危险因素。人类前列腺是 由三个解剖区组成，即外周区（PZ）、过渡区（TZ）和中央区 （CZ）. CaP主要出现在前列腺的PZ中，然后是TZ。我们的体内研究表明， 镉暴露诱发不同类型的前列腺恶性肿瘤，如TZ中的鳞状细胞癌（SCC 前列腺PZ的低分化癌（PDC）。因此，本研究的目的是了解 实验室模型中镉诱导的SCC的病理生物学和分子景观（体外和体内） 和临床标本。慢性接触镉可使前列腺细胞TZ中镉浓度升高 肿瘤（SCC）的异种移植小鼠，不同的镉诱导肿瘤（PDC）的前列腺PZ。 随后，对作用机制的分析表明，镉暴露诱导了锌- 在良性前列腺增生（BPH：TZ）细胞中，小脑指2（ZIC 2），但在RWPE-1（PZ）中不表达 细胞在分子水平上，ZIC 2与胶质瘤相关癌基因家族锌指1（GLI 1）相互作用， 下游目标的音刺猬（嘘）信号，激活亲生存机制，在镉- BPH 1细胞类似地，ZIC 2在RWPE-1细胞中的过表达导致球状体形成， 证实了ZIC 2的致癌功能。此外，我们发现ZIC 2和GLI 1的表达相应地 与BPH或邻近的健康组织相比，不同等级的CaP增加（Ehrasekaran et 例如，2020肿瘤发生）。基于这些结果，我们假设ZIC 2和GLI 1的激活是由细胞周期的变化引起的。 负责镉暴露的BPH细胞的恶性转化（SCC）。目标1：剖析机制 通过镉激活ZIC 2，并确定ZIC 2激活是否是恶性肿瘤所必需的。 BPH 1和BPH/hTERT 1细胞的转化。目的-2：确定ZIC 2和 GLI 1在镉暴露的BPH 1和BPH/hTERT 1细胞中的活化和检测其功能。目标3：研究Cd- 在小鼠模型中诱导肿瘤发生，并在人CaP样本中验证分子标记。的 研究的成功完成不仅将为填补 了解镉诱导的SCC的病理生物学，但也提供了一个深入了解的分子 与SCC相关的机制（MTF-1、ZIC 2和GLI 1信号传导）以及其他金属诱导的 恶意