Mutant Kras-induced upregulation of CD24 enhances prostate cancer stemness and bone metastasis

Weng, Ching Chieh; Ding, Pei Ya; Liu, Yu Hsuan; Hawse, John R.; Subramaniam, Malayannan; Wu, Chia Chen; Lin, Yn-Hwang; Chen, Chiao Yun; Hung, Wen Chun; Cheng, Kuang Hung

doi:10.1038/s41388-018-0575-7

Cited by 40 publications

(36 citation statements)

References 48 publications

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“…Prostate cancer (PCa) is one of the most common malignant tumors of the male genitourinary system and the second leading cause of death among men worldwide (1). There were 1,276,106 new cases and 358,989 deaths (3.8% of all deaths caused by cancer in men) associated with PCa in 2018 (2).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

Lin

et al. 2020

Int J Oncol

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Prostate cancer (PCa) is the second leading cause of cancer-related death among men worldwide. The present study aimed to investigate the role of germ cell-specific gene 2 protein (GSG2), also termed histone H3 phosphorylated by GSG2 at threonine-3, in the development and progression of PCa. GSG2 expression levels in PCa tissues and para-carcinoma tissues was detected by immunohistochemistry. The GSG2 knockdown cell model was constructed by lentivirus infection, and the knockdown efficiency was verified by qPCR and WB. In addition, the effects of shGSG2 on cell proliferation, colony formation and apoptosis were evaluated by Celigo cell counting assay, Giemsa staining and flow cytometry, respectively. Tumor development in nude mice was also detected. GSG2 expression was upregulated in PCa tissues and human PCa cell lines PC-3 and DU 145. High expression of GSG2 in tumor samples was associated with progressed tumors. GSG2 knockdown suppressed cell proliferation and colony formation, but promoted apoptosis, which was also verified in vivo.The results of the present study revealed that GSG2 upregulation was associated with PCa progression; GSG2 knockdown inhibited cell proliferation and colony formation and induced apoptosis, and may therefore serve as a potential therapeutic target for PCa therapy.

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Section: Introductionmentioning

confidence: 99%

Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

Lin

et al. 2020

Int J Oncol

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“…3D). To confirm that the PIM1‐induced stem cell signature is associated with a stemness state, we analyzed PIM1‐overexpressing cells for the enrichment of stem cell surface markers (CD24 (Weng et al , 2019), CD29 (Lawson et al , 2010; Vassilopoulos et al , 2014), and CD49B (Erb et al , 2018; Lawson et al , 2010). We demonstrate that PIM1 overexpression in PC3 cells induces stem cell surface markers CD29, CD49b, and CD24, suggesting that increased PIM1 expression is capable of inducing a stem cell‐like surface phenotype through in part regulating these gene changes (Fig.…”

Section: Resultsmentioning

confidence: 99%

PIM protein kinases regulate the level of the long noncoding RNA H19 to control stem cell gene transcription and modulate tumor growth

et al. 2020

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The proviral integration site for Moloney murine leukemia virus (PIM) serine/threonine kinases have an oncogenic and prosurvival role in hematological and solid cancers. However, the mechanism by which these kinases drive tumor growth has not been completely elucidated. To determine the genes controlled by these protein kinases, we carried out a microarray analysis in T‐cell acute lymphoblastic leukemia (T‐ALL) comparing early progenitor (ETP‐ALL) cell lines whose growth is driven by PIM kinases to more mature T‐ALL cells that have low PIM levels. This analysis demonstrated that the long noncoding RNA (lncRNA) H19 was associated with increased PIM levels in ETP‐ALL. Overexpression or knockdown of PIM in these T‐ALL cell lines controlled the level of H19 and regulated the methylation of the H19 promoter, suggesting a mechanism by which PIM controls H19 transcription. In these T‐ALL cells, the expression of PIM1 induced stem cell gene expression (SOX2, OCT‐4, and NANOG) through H19. Identical results were found in prostate cancer (PCa) cell lines where PIM kinases drive cancer growth, and both H19 and stem cell gene levels. Small molecule pan‐PIM inhibitors (PIM‐i) currently in clinical trials reduced H19 expression in both of these tumor types. Importantly, the knockdown of H19 blocked the ability of PIM to induce stem cell genes in T‐ALL cells, suggesting a novel signal transduction cascade. In PCa, increases in SOX2 levels have been shown to cause both resistance to the androgen deprivation therapy (ADT) and the induction of neuroendocrine PCa, a highly metastatic form of this disease. Treatment of PCa cells with a small molecule pan‐PIM‐i reduced stem cell gene transcription and enhanced ADT, while overexpression of H19 suppressed the ability of pan‐PIM‐i to regulate hormone blockade. Together, these results demonstrate that the PIM kinases control the level of lncRNA H19, which in turn modifies stem cell gene transcription regulating tumor growth.

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“…CD24 expression is associated with aggressive and metastatic prostate cancers 12 . Mutant Kras‐induced upregulation of CD24 enhances prostate cancer stemness and bone metastasis 13 . Recently, we identified a CD24‐p53 axis, which functions in prostate cancer cells most likely through a CD24/NPM‐ARF‐MEM2‐p53 signaling pathway 6,12 .…”

Section: Introductionmentioning

confidence: 99%

A CD24‐p53 axis contributes to African American prostate cancer disparities

et al. 2020

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Background: Using a functional analysis of prostate cancer cells, we found a CD24-dependent inactivation of mutant p53, but the clinical significance of this observation remained uncertain. Here, we validated these results with samples of human prostate cancer and explored the role of a CD24-p53 axis in racial disparities of prostate cancer.Methods: Samples of formalin-fixed, paraffin-embedded prostate cancer from 141 European Americans (EAs) and 147 African Americans (AAs) in two independent sample cohorts were assessed for protein expression of CD24, mutant p53, mouse double minute 2 human homolog (MDM2), and cyclin dependent kinase inhibitor 2A (ARF) using immunohistochemical analyses. All samples were analyzed for TP53 R175H and TP53 R273H .Results: CD24, mutant p53, MDM2, and ARF proteins were expressed in 55%, 24%, 39%, and 68% of prostate cancer samples, respectively. CD24 and mutant p53 were present more frequently in late-stage and metastatic prostate cancer. The presence of CD24 was associated with a greater than fourfold risk of metastasis, which included lymph node and distant metastases. H score analysis showed positive correlations of CD24 expression with mutant p53 (r = .308, P < .001) and MDM2 (r = .227, P = .004). There was a negative correlation for CD24 with ARF (r = −.280, P < .001). A racial disparity was evident for CD24 (AAs/EAs: 64% vs 47%; P = .004) but not for mutant p53 (AA/EA: 28% vs 21%; P = .152). In 32 CD24 + /mutant p53 + cases, a TP53 R273H mutation was found in five cases, but no TP53 R175H mutation was found. Conclusion:The CD24-p53 axis may contribute to aggressive and metastatic prostate cancers, especially those of AAs. This observation enhances understanding of the pathogenesis of prostate cancer and its associated racial disparities. K E Y W O R D SCD24, metastasis, prostate cancer, racial disparity, TP53

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Mutant Kras-induced upregulation of CD24 enhances prostate cancer stemness and bone metastasis

Cited by 40 publications

References 48 publications

Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

PIM protein kinases regulate the level of the long noncoding RNA H19 to control stem cell gene transcription and modulate tumor growth

A CD24‐p53 axis contributes to African American prostate cancer disparities

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