Elucidating the molecular signaling of Cadmium Carcinogenesis

阐明镉致癌的分子信号传导

• 批准号: 10633057
• 负责人: Chendil Damodaran
• 金额: $ 49.95万
• 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/10633057
• 关键词: Anatomy; Apoptotic; Benign Prostatic Hypertrophy; Binding; Blood; CRISPR/Cas technology; Cadmium; Cancer Patient; Carcinogens; Carcinoma; Cells; Cerebellum; Chronic; Clinical; Development; Dose; Epidemiology; Exposure to; GLI Family Protein; Goals; Health; Human; In Vitro; Knockout Mice; Knowledge; Laboratories; Malignant - descriptor; Malignant neoplasm of prostate; Measures; Metals; Modeling; Molecular; Mus; Oncogenic; Patients; Pattern; Peripheral; 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; carcinogenesis; cohort; exposed human population; genetic approach; in vivo; inducible Cre; innovation; insight; molecular marker; mouse model; overexpression; pharmacologic; 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.

项目摘要/摘要 镉（CD）是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 由三个解剖区域组成，即外围区（PZ），过渡区（TZ）和中央区域 （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 CD-暴露诱导了不同类型的前列腺恶性肿瘤，例如TZ中的鳞状细胞癌（SCC） 前列腺PZ中分化不足的癌（PDC）。因此，研究的目的是了解 在实验室模型中CD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。在形成的前列腺细胞Tz中的血浆浓度的长期暴露 异种移植小鼠中的肿瘤（SCC）与前列腺PZ中的CD诱导的肿瘤（PDC）不同。 随后，对作用机理的分析表明，CD暴露诱导了锌的表达 良性前列腺增生（BPH：TZ）细胞中小脑2（ZIC2）的手指，但在RWPE-1（PZ）中不在 细胞。在分子水平上，ZIC2与神经胶质瘤相关的癌基因家族锌指1（GLI1），A Sonic刺猬（SHH）信号的下游靶标，该靶标在CD-中激活促生存的机械 暴露的BPH1细胞。同样，RWPE-1细胞中ZIC2的过表达导致球体形成， 确认ZIC2的致癌功能。另外，我们发现ZIC2和GLI1表达式相应 与BPH或邻近的健康组织相比，不同等级的CAP的增加（Chandrasekaran et Al。，2020年发生）。基于这些结果，我们假设ZIC2和GLI1的激活是 负责CD暴露BPH细胞的恶性转化（SCC）。目标1：剖析机制 CD激活ZIC2并确定ZIC2激活是否对恶性肿 BPH1和BPH/HTERT1细胞的转化。 AIM-2：确定ZIC2和 Gli1激活并检查其在CD暴露的BPH1和BPH/HTERT1细胞中的功能。目标3：研究CD- 在小鼠模型中诱导的肿瘤发生并验证人帽标本中的分子标记。这 成功完成研究不仅将为填补填充的空白提供新的信息 有关CD诱导的SCC病理生物学的知识，但也提供了对分子的见解 与SCC以及其他金属诱导的机理（MTF-1，ZIC2和GLI1信号传导） 恶性。