PiRNA-4447944 promotes castration-resistant growth and metastasis of prostate cancer by inhibiting NEFH expression through forming the piRNA-4447944-PIWIL2-NEFH complex

Sep 21, 2026

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Castration-resistant prostate cancer (CRPC) drives mortality after androgen deprivation therapy (ADT) fails. PIWI-interacting RNAs are recognized regulators in human cancers, yet their expression landscape and functional roles in CRPC remain unclear. Using small RNA sequencing across benign tissues and paired hormone-sensitive versus CRPC samples, PIRNA-4447944 is identified as highly expressed in CRPC. Overexpression supports castration resistance in vitro and in vivo, while antisense knockdown suppresses CRPC proliferation, migration, and invasion. Mechanistically, piR-4447944 forms a PIWIL2-associated complex and inhibits NEFH post-transcriptionally, promoting androgen-independent tumor growth and suggesting therapeutic potential.

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CategoryHealthcare

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Ivyspring International Publisher InternationalJournal of Biological Sciences 2024; 20(9): 3638-3655. doi: 10.7150/ijbs.96173 Research Paper PiRNA-4447944 promotes castration-resistant growth and metastasis of prostate cancer by inhibiting NEFH expression through forming the piRNA-4447944-PIWIL2-NEFH complex Qiang Peng1*, Yu Chen2,3,4*, Tingting Xie1, Dandan Pu5, Vincy Wing-Sze Ho1, Jingkai Sun1, Kang Liu1, Ronald Cheong-Kin Chan6, Xiaofan Ding7, Jeremy Yuen-Chun Teoh1, Xin Wang8, Peter Ka-Fung Chiu1􀀍, Chi-Fai Ng1􀀍 1. SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China. 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China. 3. Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, China. 4. HitGen Inc., Building 6, No.8 Huigu First East Road, Tianfu International Bio-Town, Shuangliu District, Chengdu, Sichuan, China. 5. Department of Surgery, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China. 6. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China. 7. Faculty of Health Sciences, University of Macau, Macau, China. 8. Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China. *These authors contributed equally to this work. 􀀍 Corresponding author: Prof Peter Ka-Fung CHIU, SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China. Address: Department of Surgery, 4/F, LCW Clinical Sciences Building, Prince of Wales Hospital, Shatin, Hong Kong, China. Tel. +852 35052625; Fax: +852 26353487; Email: [peterchiu@surgery.cuhk.edu.hk. Prof Chi-Fai NG](peterchiu@surgery.cuhk.edu.hk. Prof Chi-Fai NG), SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China. Address: Department of Surgery, 4/F, LCW Clinical Sciences Building, Prince of Wales Hospital, Shatin, Hong Kong, China. Tel. +852 35052625; Fax: +852 26353487; [Email: ngcf@surgery.cuhk.edu.hk](Email: ngcf@surgery.cuhk.edu.hk). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [http://ivyspring.com/terms](http://ivyspring.com/terms) for full terms and conditions. Received: 2024.03.11; Accepted: 2024.06.11; Published: 2024.07.01 Abstract Castration-resistant prostate cancer (CRPC) is the leading cause of prostate cancer (PCa)-related death in males, which occurs after the failure of androgen deprivation therapy (ADT). PIWI-interacting RNAs (piRNAs) are crucial regulators in many human cancers, but their expression patterns and roles in CRPC remain unknown. In this study, we performed small RNA sequencing to explore CRPC-associated piRNAs using 10 benign prostate tissues, and 9 paired hormone-sensitive PCa (HSPCa) and CRPC tissues from the same patients. PiRNA-4447944 (piR-4447944) was discovered to be highly expressed in CRPC group compared with HSPCa and benign groups. Functional analyses revealed that piR-4447944 overexpression endowed PCa cells with castration resistance ability in vitro and in vivo, whereas knockdown of piR-4447944 using anti-sense RNA suppressed the proliferation, migration and invasion of CRPC cells. Additionally, enforced piR-4447944 expression promoted in vitro migration and invasion of PCa cells, and reduced cell apoptosis. Mechanistically, piR-4447944 bound to PIWIL2 to form a piR-4447944/PIWIL2 complex and inhibited tumor suppressor NEFH through direct interaction at the post-transcriptional level. Collectively, our study indicates that piR-4447944 is essential for prostate tumor-propagating cells and mediates androgen-independent growth of PCa, whi

FAQs

What is castration-resistant prostate cancer (CRPC) in this study context?

CRPC is the more aggressive form of prostate cancer that emerges after failure of androgen deprivation therapy (ADT).

How was piRNA-4447944 identified and evaluated in CRPC?

The study used small RNA sequencing on benign tissues and paired hormone-sensitive and CRPC tissues, followed by functional experiments assessing effects of piR-4447944 overexpression and knockdown.

What mechanism links piR-4447944 to CRPC progression?

piR-4447944 binds PIWIL2 to form a piR-4447944/PIWIL2 complex and inhibits the tumor suppressor NEFH at the post-transcriptional level.

Sep 21, 2026

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