LIN28B promotes the development of neuroendocrine prostate cancer.

Abstract

Therapy-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive subtype of prostate cancer with poor patient survival. Emerging evidence indicates that t-NEPC can develop when prostate adenocarcinoma cells acquire cancer stem-like cell signaling in the presence of androgen receptor inhibition, followed by redifferentiation toward neuroendocrine lineage and subsequent t-NEPC progression. Whether the stem-like signaling is controlled by the core pluripotency stem cell genes (e.g., LIN28 and SOX2) remains unknown. Here, we report that the transcription of the LIN28B isoform and SOX2 were co-upregulated in t-NEPC patient tumors, patient-derived xenografts, transgenic mice, and cell models. Immunohistochemistry validated that LIN28B and SOX2 protein expression were elevated in t-NEPC patient biopsies. Using prostate adenocarcinoma and t-NEPC cell models, we demonstrated that LIN28B induced a stem-like gene network, neuroendocrine biomarkers, and neuroendocrine cell morphology. LIN28B depletion by CRISPR inhibited t-NEPC tumorigenesis and xenograft growth. These LIN28B functions were mediated mainly through the suppression of let-7 miRNA expression, resulting in de-repression of the transcription factor HMGA2 and HMGA2-mediated SOX2 expression. This study revealed a mechanism by which t-NEPC can develop through the LIN28B/let-7/SOX2 axis that regulates a cancer cell stem-like gene network, highlighting LIN28B as a potential therapeutic target in t-NEPC.

• Authors: Jessica Lovnicki, Yu Gan, Tingting Feng, Yinan Li, Ning Xie, Chia-Hao Ho, Ahn R Lee, Xufeng Chen, Lucia Nappi, Bo Han, Ladan Fazli, Jiaoti Huang, Martin E Gleave, Xuesen Dong
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 10 Pg. 5338-5348 (10 01 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 32634132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• HMGA2 Protein
• HMGA2 protein, human
• LIN28B protein, human
• MicroRNAs
• RNA-Binding Proteins
• SOX2 protein, human
• SOXB1 Transcription Factors
• mirnlet7 microRNA, human

Topics

• Animals
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• HMGA2 Protein (genetics, metabolism)
• Heterografts
• Humans
• Male
• Mice
• Mice, Nude
• Mice, Transgenic
• MicroRNAs (genetics, metabolism)
• Neoplastic Stem Cells (metabolism)
• Neuroendocrine Tumors (etiology, genetics, metabolism)
• Prostatic Neoplasms (etiology, genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• SOXB1 Transcription Factors (genetics, metabolism)
• Up-Regulation