Abstract 2792: PiRNA as a novel therapeutic in hepatocellular carcinoma: insights from population screening
Authors: Rui Han, Qin Qin, Ran Liu, Tianshu Wu, Yaya Guo, Peyton Cook, Kinsey Garofalo, Yujuan Guo, Bolni Nagalo, Yong Zhu
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related death globally and is the fastest-growing cause of cancer-related deaths in the United States. Current therapies, such as chemotherapy and radiotherapy, are largely ineffective in advanced HCC due to tumor-specific characteristics, resistance to drugs and radiation, and substantial adverse effects. Despite breakthroughs in immunotherapy, approximately 80-85% of American patients with advanced HCC fail to respond to treatments. These challenges underscore the urgent need for more effective therapeutic strategies to treat HCC. One emerging therapeutic strategy involves the use of small non-coding RNAs (ncRNAs), which have shown promising efficacy in both preclinical and clinical studies for various cancer types. Piwi-interacting RNAs (piRNAs) are an abundant of small non-coding RNAs (ncRNAs) involved in maintaining genomic stability and represent a promising but largely unexplored avenue for cancer treatment. The current study identified a piRNA candidate and examined its therapeutic implication for the treatment of HCC. First, we performed piRNA arrays for small RNAs isolated from 12 pairs of HCC tissues and normal liver tissues and detected significantly downregulated piRNAs in HCC tissues compared to normal liver tissues. Downregulation of piR-37213 was confirmed using the TCGA small RNA-seq data of HCC tissues (N=331) and normal liver tissues (N=48). Lipid nanoparticles (LNP) were used as a delivery vehicle to capsulate piR-37213 in functional tests. Significant tumor-suppressing effects of piR-37213 were observed in a series of in vitro assays (P&amp;lt;0.01), including cell proliferation assays, colony formation assays, 3D formation and invasion assays. Systemic delivery of LNP-piR-37213 was administered in animal experiments. Mice (N=44) were treated twice a week for four consecutive weeks via tail vein injection. Tumor signals were significantly reduced by 90% P&amp;lt;0.001) after 2 weeks of treatment. Survival was significantly improved (P&amp;lt;0.05). Both in vitro and in vivo experiments suggest that the identified piRNA candidates, which are downregulated in HCC tissues, play a tumor-suppressing role. A genome-wide expression profiling analysis was further performed and found that genes involved in cell cycle proliferation, replication, and DNA repair were significantly downregulated, which further provided molecular mechanisms accounting for the anti-tumor effect of under-expressed piR-37213. This preclinical study represents the crucial initial step in developing a novel, piRNA-based therapeutic strategy for liver cancer and provides proof of principle for the use of piRNAs in future clinical treatment. Future studies are needed to explore the transformative potential of this early-stage, highly innovative, piRNA-based technology in cancer treatment. Citation Format: Rui Han, Qin Qin, Ran Liu, Tianshu Wu, Yaya Guo, Peyton Cook, Kinsey Garofalo, Yujuan Guo, Bolni Nagalo, Yong Zhu. PiRNA as a novel therapeutic in hepatocellular carcinoma: insights from population screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2792.