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LIN28B confers cancer stem-like phenotypes for neuroendocrine prostate cancer progression

University of British Columbia

Due to the increased utilization of next generation anti-androgens to treat prostate adenocarcinoma (AdPC), therapy-induced neuroendocrine prostate cancer (t-NEPC) has become more prevalent. Although the mechanisms by which t-NEPC is established are not fully understood, emerging evidence suggests that AdPC cells can gain an intermediate pluripotent stem cell (SC)-like phenotype that can promote t-NEPC development. However, it remains unclear whether the core embryonic stem cell genes (ESCs) (LIN28, POU5F1, SOX2, and NANOG) regulate the stem-like state of prostate cancer cells and the switch from luminal epithelial to neuroendocrine lineage during the transition from AdPC to t-NEPC. We hypothesize that LIN28B plays a key role in the transition from AdPC to t-NEPC, and that the overexpression of LIN28B may promote proliferation and trans-differentiation, which may contribute to t-NEPC progression. By comparing the published RNA-seq data on AdPC and t-NEPC, we found that approximately 50% of t-NEPC patient tumors have gained LIN28B and SOX2 expression. Standard molecular and cellular biology techniques were applied to characterize the functions of LIN28B and its relationship with SOX2 using t-NEPC cell and xenograft models. We found that the mRNA levels of LIN28B and SOX2 are positively correlated in patient tumors, patient derived xenografts, transgenic mice, and multiple cell models. LIN28B and SOX2 expression was confirmed to be co-upregulated in a subset of t-NEPC patients by immunohistochemistry. Using our clinically relevant t-NEPC cell/xenograft model, DuNE, we demonstrated that LIN28B is essential for stem cell-like and neuroendocrine marker expression and cell morphology. LIN28B gene depletion by CRISPR inhibited DuNE xenograft initiation and tumor growth. These LIN28B functions are mainly mediated by its inhibitory effects on the microRNA let-7d, which resulted in the upregulation of HMGA2 and HGMA2 mediated SOX2 transcription. Overall, this thesis work adds to the understanding that the LIN28B/let-7/SOX2 axis is an important signaling pathway that regulates a cancer stem-like phenotype to promote t-NEPC development. Ultimately, this knowledge pertains to the clinical implications of LIN28B in informing future therapies that will be effective for managing t-NEPC.

Text

2019-08-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71328

Reproductive and Developmental Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/