Expression and prognostic value of transcription factor PROX1 in colorectal cancer

Skog, Maria S.; Bono, Petri; Lundin, Mikael; Lundin, Johan; Louhimo, Johanna; Linder, Nina; Petrova, Tatiana V.; Andersson, Leif C.; Joensuu, Heikki; Alitalo, Kari; Haglund, Caj

doi:10.1038/bjc.2011.297

Cited by 52 publications

(62 citation statements)

References 21 publications

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“…S4D; Table 1). Some cytoplasmic PROX1 staining was observed, but this is not an unusual occurrence (Duncan et al 2002;Bosco et al 2005;Laerm et al 2007;Gill et al 2009;Yamazaki et al 2009;Dashkevich et al 2010;da Cunha Castro and Galambos 2011;Skog et al 2011). Similarly, VEGFR-3-positive LAM cells were detected in all cases, with greater percentages and more intense immunoreaction in late-stage LAM (mean, 76%; range, 61%-100%) than in early-stage LAM (mean, 50%; range, 40%-75%; p<0.0001) (Fig.…”

Section: Resultsmentioning

confidence: 80%

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

Davis

Hyjek

Husain

et al. 2013

J Histochem Cytochem.

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Pulmonary lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm affecting almost exclusively women of childbearing age. LAM belongs to the family of perivascular epithelioid cell tumors, characterized by spindle and epithelioid cells with smooth muscle and melanocytic differentiation. LAM cells infiltrate the lungs, producing multiple, bilateral lesions rich in lymphatic channels and forming cysts, leading to respiratory insufficiency. Here we used antibodies against four lymphatic endothelial markers—podoplanin (detected by D2-40), prospero homeobox 1 (PROX1), vascular endothelial growth factor receptor 3 (VEGFR-3), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1)—to determine whether LAM cells show lymphatic differentiation. Twelve of 12 diagnostic biopsy specimens (early-stage LAM) and 19 of 19 explants (late-stage LAM) showed immunopositivity for D2-40 in most neoplastic cells. PROX1, VEGFR-3, and LYVE1 immunoreactivity varied from scarce in the early stage to abundant in the late stage. Lymphatic endothelial, smooth muscle, and melanocytic markers were partially co-localized. These findings indicate that lymphatic endothelial differentiation is a feature of LAM and provide evidence of a previously unidentified third lineage of differentiation in this neoplasm. This study has implications for the histological diagnosis of LAM, the origin of the neoplastic cells, and potential future treatment with drugs targeting lymphangiogenesis.

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Section: Resultsmentioning

confidence: 80%

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

Davis

Hyjek

Husain

et al. 2013

J Histochem Cytochem.

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“…Decreased expression of PROX1 is observed in pancreatic cancers, hepatocellular carcinomas, sporadic breast cancers, and biliary carcinomas, indicating that PROX1 plays a tumor-suppressive role in these cancers [9][10][11][12]. In contrast, overexpression of PROX1 is observed in colorectal cancers, endothelial tumors, and gliomas, indicating that PROX1 promotes the progression of these cancers [13][14][15][16]. These data suggest that PROX1 could be a potential molecular target for treating human cancers.…”

Section: Introductionmentioning

confidence: 65%

“…Previously, immunostaining of PROX1 protein showed both nuclear and cytoplasmic expression in gastric cancer, and cytoplasmic expression of PROX1 protein correlated with its mRNA amplification [35]. However, in colorectal cancer, expression of PROX1 protein was limited to tumor cell nuclei [13]. PROX1 is a transcription factor and its level and subcellular localization may be dynamically changed during carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Prospero homeobox 1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis

et al. 2016

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Background Prospero homeobox 1 (PROX1) functions as a tumor suppressor gene or an oncogene in various cancer types. However, the distinct function of PROX1 in gastric cancer is unclear. We determined whether PROX1 affected the oncogenic behavior of gastric cancer cells and investigated its prognostic value in patients with gastric cancer. Methods A small interfering RNA against PROX1 was used to silence PROX1 expression in gastric cancer cell lines AGS and SNU638. Expression of PROX1 in gastric cancer tissues was investigated by performing immunohistochemistry. Apoptosis, proliferation, angiogenesis, and lymphangiogenesis were determined by performing the TUNEL assay and immunohistochemical staining for Ki-67, CD34, and D2-40. Results PROX1 knockdown induced apoptosis by activating cleaved caspase-3, caspase-7, caspase-9, and poly(ADP-ribose) polymerase, and by decreasing the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL. PROX1 knockdown also suppressed tumor cell proliferation. In addition, PROX1 knockdown decreased lymphatic endothelial cell invasion and tube formation and the expression of vascular endothelial growth factor (VEGF)-C and -D and cyclooxygenase (COX)-2. However, PROX1 knockdown only decreased umbilical vein endothelial cell invasion, not tube formation. The mean Ki-67 labeling index and lymphatic vessel density value of PROX1-positive tumors were significantly higher than those of PROX1-negative tumors. However, no significant difference was observed between PROX1 expression and apoptotic index or microvessel density. PROX1 expression was significantly associated with age, cell differentiation, lymph node metastasis, cancer stage, and poor survival. Conclusions These results indicate that PROX1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis.

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“…Strong expression of PROX1 was associated with metastatic potential, poor patient survival and high WHO grade. In colorectal adenocarcinomas, PROX1 predicts aggressive clinical course and poor survival [7]. In Kaposiform hemangioendothelioma, overexpression of PROX1 is associated with more aggressive tumor behaviour by inducing genes involved in cell migration and adhesion, thus enabling infiltration into surrounding tissues [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…In normal colon, PROX1 is expressed mostly in neuroendocrine epithelial cells and lymphatic vessel endothelial cells [7]. At least 15 different subpopulations of neuroendocrine cells have been detected in the gastrointestinal (GI) tract.…”

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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Expression and prognostic value of transcription factor PROX1 in colorectal cancer

Cited by 52 publications

References 21 publications

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

Prospero homeobox 1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis

PROX1 is involved in progression of rectal neuroendocrine tumors, NETs

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