Prox1 Promotes Expansion of the Colorectal Cancer Stem Cell Population to Fuel Tumor Growth and Ischemia Resistance

Wiener, Zoltán; Högström, Jenny; Hyvönen, Ville; Band, Arja M.; Kallio, Pentti; Holopainen, Tanja; Dufva, Olli; Haglund, Caj; Kruuna, Olli; Oliver, Guillermo; Ben‐Neriah, Yinon; Alitalo, Kari

doi:10.1016/j.celrep.2014.08.034

Cited by 65 publications

(69 citation statements)

References 40 publications

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“…8–10 The PROX1 WRE is located approximately 40-kb upstream of the PROX1 promoter (Figure 2e), 8 but the mechanism by which these two elements communicate is not known. Given our finding that Pol II is associated with the PROX1 WRE, we hypothesized that the WRE may be in close proximity to the PROX1 promoter.…”

Section: Resultsmentioning

confidence: 99%

“…Given previous studies showing that PROX1 contributes to metastasis by regulating the transcriptional network in CRC 8–10 and our findings that DBC1 is an essential coactivator for PROX1 expression, we investigated the global effect of loss of DBC1 on the expression of PROX1 target genes. In line with the downregulation of PROX1 expression upon loss of DBC1 (Figure 1g and Supplementary Figure S10a), GSEA using the PROX1 gene signature revealed significant deregulation of PROX1 target gene expression in WT versus DBC1 KO SW480 cells (Figure 4a and Supplementary Figures S3c and d).…”

Section: Resultsmentioning

confidence: 99%

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Positive regulation of β-catenin–PROX1 signaling axis by DBC1 in colon cancer progression

Kim

et al. 2015

Oncogene

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Aberrant activation of Wnt/β-catenin pathway contributes to colorectal cancer (CRC) progression. However, little is known about regulatory mechanisms of the β-catenin activity in cancer progression. Here we investigated the role of DBC1, which was recently reported as a negative regulator of SIRT1 and a transcriptional coactivator, in the regulation of Wnt/β-catenin signaling. We identified the genome-wide targets of DBC1 and found that loss of DBC1 inhibits the expression of β-catenin target genes including PROX1, a transcription factor linked to CRC progression. Mechanistically, DBC1 stabilizes LEF1–β-catenin interaction by inhibiting SIRT1-mediated β-catenin deacetylation, thereby enhancing LEF1–β-catenin complex formation and long-range chromatin looping at the PROX1 locus. Furthermore, DBC1 is also required for the transcriptional activity of PROX1, suggesting that DBC1 has a dual function in regulating β-catenin–PROX1 signaling axis: as a coactivator for both β-catenin and PROX1. Importantly, loss of DBC1 inhibited growth and tumorigenic potential of colon cancer cells, and DBC1 expression correlated with shorter relapse-free survival in patients with advanced CRC. Our results firmly establish DBC1 as a critical positive regulator of β-catenin–PROX1 signaling axis and a key factor in β-catenin–PROX1-mediated CRC progression.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Positive regulation of β-catenin–PROX1 signaling axis by DBC1 in colon cancer progression

Kim

et al. 2015

Oncogene

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“…PROX1 has previously been associated with Wnt/β-catenin signaling in different cancer cells. Harboring TCF/LEF binding sites in its upstream region, the PROX1 gene was found to be directly regulated by Wnt/β-catenin signaling in colon cancer cells (29–31). More recently, PROX1 has been reported to promote HCC cell proliferation by upregulating β-catenin and enhancing its nuclear localization (42).…”

Section: Disucssionmentioning

confidence: 99%

Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells

et al. 2016

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Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/β-catenin signaling, but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 re-expression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma, and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression

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“…When non-neoplastic intestinal mucosa transforms into an adenoma, and further into invasive adenocarcinoma, PROX1 contributes to tumor progression, likely via modulating cell adhesion and extracellular matrix interactions [4,5]. Annexin A1 is a target of the Wnt pathway; overexpression of PROX1 leads to diminished expression of Annexin A1 [6].…”

Section: Introductionmentioning

confidence: 99%

PROX1 is involved in progression of rectal neuroendocrine tumors, NETs

et al. 2015

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PROX1 is a homeobox transcription factor involved in the development of the lens, liver and heart and found upregulated in colorectal cancers. We studied PROX1 expression by immunohistochemistry in rectal neuroendocrine tumors (NETs). Approximately 10 to 15 % of gastroenteropancreatic NETs occur in the rectum, and some may metastasize. Yet little is known about the molecular pathogenesis of rectal NETs or their metastasis propensity. The objectives were to find out whether PROX1 plays a role in progression of rectal NETs and whether it has value as prognostic marker. In grading of rectal NETs, we applied the WHO 2010 classification. We carried out immunohistochemical staining of PROX1 on 72 primary tumors and six metastases and evaluated nuclear positivity in each tumor. Correlation between PROX1 expression, metastasis and patient survival was then assessed. Annexin A1, a downstream target of PROX1, was immunohistochemically assessed in 18 tumors. PROX1 protein was detected in about half of the tumors, with stronger expression in metastasized cases. PROX1 expression correlated with tumor metastasis and patient prognosis. Annexin A1 was negative in most of the high-grade tumors correlating strongly with grade and metastatic potential. Our results indicate that immunohistochemical detection of PROX1 correlates with a more malignant phenotype in rectal NETs. High PROX1 expression was associated with increased metastatic potential and poor patient survival but not as strongly as grade by the WHO 2010 classification. PROX1 may be involved in progression of rectal NETs as a part of the Wnt pathway.

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Prox1 Promotes Expansion of the Colorectal Cancer Stem Cell Population to Fuel Tumor Growth and Ischemia Resistance

Cited by 65 publications

References 40 publications

Positive regulation of β-catenin–PROX1 signaling axis by DBC1 in colon cancer progression

Positive regulation of β-catenin–PROX1 signaling axis by DBC1 in colon cancer progression

Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells

PROX1 is involved in progression of rectal neuroendocrine tumors, NETs

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