Elucidating the molecular signaling of Cadmium Carcinogenesis

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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.