Elucidating the molecular signaling of Cadmium Carcinogenesis

项目摘要/摘要 镉(Cd)是一种已知的人类致癌物质，也是前列腺癌(CAP)的危险因素。人类的前列腺是 由三个解剖区组成，即外围区(PZ)、过渡区(TZ)和中心区 (Cz)。CAP主要发生在前列腺的PZ，其次是TZ。我们的活体研究表明 镉暴露诱发不同类型的前列腺癌，如TZ鳞状细胞癌 和前列腺癌(PZ)中的低分化癌(PDC)。因此，这项研究的目标是了解 体外和体内镉诱发鳞癌的病理生物学和分子生物学研究 和临床标本。慢性镉暴露对前列腺细胞TZ内Cd浓度的影响 异种移植小鼠的肿瘤(SCC)不同于Cd诱导的肿瘤(PDC)在前列腺的PZ。 随后，对作用机制的分析表明，镉暴露诱导了锌的表达。 在良性前列腺增生症(BPH：TZ)细胞中的小脑2指(ZIC2)，但在RWPE-1(PZ)中不表达 细胞。在分子水平上，ZIC2与胶质瘤相关癌基因家族锌指蛋白1(GLI1)相互作用。 Sonic Hedgehog(Shh)信号的下游靶标，它激活CD-1中的促生存机制。 暴露的BPH1细胞。同样，ZIC2在RWPE-1细胞中过表达导致球体形成， 证实了ZIC2的致癌功能。此外，我们还发现ZIC2和GLI1的表达相应地 与良性前列腺增生症或邻近的健康组织相比，不同级别的帽状物增加(Chandrasekaran et 等，2020肿瘤发生)。根据这些结果，我们假设ZIC2和GLI1的激活是 负责镉暴露的BPH细胞的恶性转化(SCC)。目标1：剖析机制 Cd激活ZIC2并确定ZIC2激活是否是恶性肿瘤所必需的 BPH1和BPH/hTERT1细胞的转化。目的-2：确定ZIC2和ZIC2之间的分子相互作用 Cd对BPH1和BPH/hTERT1细胞Gli1激活及其功能的影响目标3：研究CD- 在小鼠模型中诱导肿瘤形成，并在人类帽子样本中验证分子标记。这个 这些研究的成功完成不仅将有助于提供新的信息来填补 关于镉诱导的鳞状细胞癌的病理生物学的知识，但也提供了对分子的洞察 与鳞状细胞癌及其他金属相关的机制(MTF-1、ZIC2和GLI1信号) 恶性疾病。

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.