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bioRxiv · 10.1101/2025.02.06.636957

siRNA-based Therapeutic Candidate Targeting PRDM2 for Inhibition of Lung Cancer Progression

Kumar, S.·Malik, M. Z.·Chaturvedi, M.·Mishra, M.·Donato, M. D.·Casamassimi, A.·Abbondanza, C.·Gazzerro, P.·Nguyen, C.·Nunez, N. N.·Sen, S.·Niles, B.·Chaturvedi, R.
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Abstract

Lung cancer is the leading cause of tumor-related fatalities worldwide. The current precision therapies are effective but target only those molecules that are impacted in a minority of lung cancer patients. Positive Regulatory Domain 2 (PRDM2), a member of the PRDM gene family, also known as Retinoblastoma Interacting Zinc finger (RIZ) protein. RIZ is found to be misregulated in more than 60% of lung cancer patients, representing a significantly affected population when compared to other mutation-prone oncogenic factors. RIZ expresses two contrasting variants, a tumor suppressor RIZ1, and an oncogenic RIZ2 protein. In lung cancer, the RIZ1/RIZ2 ratio alters, and the epigenetic silencing of RIZ1 promotes RIZ2 overexpression. In this study, we used siRNA (ARIZ-047) to knockdown and inhibit the effect of the oncogenic protein RIZ2. Inhibiting RIZ2 with ARIZ-047 treatment increased RIZ1 expression and decreased the viability of a lung cancer cell line (A549). The ARIZ-047 treatment also upregulated the negative regulators of the Wnt signaling pathway and restrained the tumor progression in the xenograft mice model. In conclusion, this study identifies ARIZ-047 as a targeted therapy in lung cancer, which specifically inhibits RIZ2 and suggests the role of the Wnt signaling pathway in RIZ2 overexpression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/636957v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1a5eb34org.highwire.dtl.DTLVardef@1f4dc2forg.highwire.dtl.DTLVardef@a3ce29org.highwire.dtl.DTLVardef@33f576_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kumar, S., Malik, M. Z., Chaturvedi, M., Mishra, M., Donato, M. D., Casamassimi, A., Abbondanza, C., Gazzerro, P., Nguyen, C., Nunez, N. N., Sen, S., Niles, B., Chaturvedi, R.. 2025-02-08. siRNA-based Therapeutic Candidate Targeting PRDM2 for Inhibition of Lung Cancer Progression. https://doi.org/10.1101/2025.02.06.636957

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