Dataset Information

Human Epididymis Protein 4 Promotes Events Associated with Metastatic Ovarian Cancer via Regulation of the Extracelluar Matrix.

ABSTRACT: Human epididymis protein 4 (HE4) has received much attention recently due to its diagnostic and prognostic abilities for epithelial ovarian cancer. Since its inclusion in the Risk of Ovarian Malignancy Algorithm (ROMA), studies have focused on its functional effects in ovarian cancer. Here, we aimed to investigate the role of HE4 in invasion, haptotaxis, and adhesion of ovarian cancer cells. Furthermore, we sought to gain an understanding of relevant transcriptional profiles and protein kinase signaling pathways mediated by this multifunctional protein. Exposure of OVCAR8 ovarian cancer cells to recombinant HE4 (rHE4) promoted invasion, haptotaxis toward a fibronectin substrate, and adhesion onto fibronectin. Overexpression of HE4 or treatment with rHE4 led to upregulation of several transcripts coding for extracellular matrix proteins, including SERPINB2, GREM1, LAMC2, and LAMB3. Gene ontology indicated an enrichment of terms related to extracellular matrix, cell migration, adhesion, growth, and kinase phosphorylation. LAMC2 and LAMB3 protein levels were constitutively elevated in cells overexpressing HE4 and were upregulated in a time-dependent manner in cells exposed to rHE4 in the media. Deposition of laminin-332, the heterotrimer comprising LAMC2 and LAMB3 proteins, was increased in OVCAR8 cells treated with rHE4 or conditioned media from HE4-overexpressing cells. Enzymatic activity of matriptase, a serine protease that cleaves laminin-332 and contributes to its pro-migratory functional activity, was enhanced by rHE4 treatment in vitro. Proteomic analysis revealed activation of focal adhesion kinase signaling in OVCAR8 cells treated with conditioned media from HE4-overexpressing cells. Focal adhesions were increased in cells treated with rHE4 in the presence of fibronectin. These results indicate a direct role for HE4 in mediating malignant properties of ovarian cancer cells and validate the need for HE4-targeted therapies that will suppress activation of oncogenic transcriptional activation and signaling cascades.

SUBMITTER: Ribeiro JR

PROVIDER: S-EPMC5786890 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Human Epididymis Protein 4 Promotes Events Associated with Metastatic Ovarian Cancer <i>via</i> Regulation of the Extracelluar Matrix.

Ribeiro Jennifer R JR Gaudet Hilary M HM Khan Mehreen M Schorl Christoph C James Nicole E NE Oliver Matthew T MT DiSilvestro Paul A PA Moore Richard G RG Yano Naohiro N

Frontiers in oncology 20180122

Human epididymis protein 4 (HE4) has received much attention recently due to its diagnostic and prognostic abilities for epithelial ovarian cancer. Since its inclusion in the Risk of Ovarian Malignancy Algorithm (ROMA), studies have focused on its functional effects in ovarian cancer. Here, we aimed to investigate the role of HE4 in invasion, haptotaxis, and adhesion of ovarian cancer cells. Furthermore, we sought to gain an understanding of relevant transcriptional profiles and protein kinase s ...[more]

PMID: 29404274

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Project description:BackgroundMetastasis-associated protein 1 (MTA1), the founding member of the MTA family of genes, can modulate transcription by influencing the status of chromatin remodeling. Despite its strong correlation with the metastatic potential of cancer cells, MTA1 can also regulate crucial cellular pathways by modifying the acetylation status. We have previously reported the presence of MTA1/MTA1 in human and mouse testes, providing the evidence for its involvement in the regulation of testicular function during murine spermatogenesis. The objective of present study was to further assess the localization of MTA1 in mouse epididymis on both transcriptional and translational level, and then to explore whether MTA1 expression is regulated by androgens and postnatal epididymal development.Methodology/principal findingsMice were deprived of circulating androgen by bilaterally castration and were then supplemented with exogenous testosterone propionate for one week. MTA1 was immunolocalized in the epithelium of the entire epididymis with the maximal expression in the nuclei of principal cells and of clear cells in proximal region. Its expression decreased gradually after castration, whereas testosterone treatment could restore the expression, indicating that the expression of this gene is dependent on androgen. During postnatal development, the protein expression in the epididymis began to appear from day 7 to day 14, increased dramatically from postnatal day 28, and peaked at adulthood onwards, coinciding with both the well differentiated status of epididymis and the mature levels of circulating androgens. This region- and cell-specific pattern was also conservative in normal human epididymis.ConclusionsOur data suggest that the expression of MTA1 protein could be regulated by androgen pathway and its expression level is closely associated with the postnatal development of the epididymis, giving rise to the possibility that this gene plays a potential role in sperm maturation and fertility.

Project description:Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are important for the secretion, activation, and function of mature TGFβ, especially so in cancer cell physiology. However, specific roles of the LTBPs remain understudied in the context of the primary tumor microenvironment. Herein, we investigated the role of LTBP3 in the distinct processes involved in cancer metastasis. By using three human tumor cell lines of different tissue origin (epidermoid HEp-3 and prostate PC-3 carcinomas and HT-1080 fibrosarcoma) and several metastasis models conducted in both mammalian and avian settings, we show that LTBP3 is involved in the early dissemination of primary cancer cells, namely in the intravasation step of the metastatic cascade. Knockdown of LTBP3 in all tested cell lines led to significant inhibition of tumor cell intravasation, but did not affect primary tumor growth. LTBP3 was dispensable in the late steps of carcinoma cell metastasis that follow tumor cell intravasation, including vascular arrest, extravasation, and tissue colonization. However, LTBP3 depletion diminished the angiogenesis-inducing potential of HEp-3 cells in vivo, which was restorable by exogenous delivery of LTBP3 protein. A similar compensatory approach rescued the dampened intravasation of LTBP3-deficient HEp-3 cells, suggesting that LTBP3 regulates the induction of the intravasation-supporting angiogenic vasculature within developing primary tumors. Using our recently developed microtumor model, we confirmed that LTBP3 loss resulted in the development of intratumoral vessels with an abnormal microarchitecture incompatible with efficient intravasation of HEp-3 carcinoma cells. Collectively, these findings demonstrate that LTBP3 represents a novel oncotarget that has distinctive functions in the regulation of angiogenesis-dependent tumor cell intravasation, a critical process during early cancer dissemination. Our experimental data are also consistent with the survival prognostic value of LTBP3 expression in early-stage head and neck squamous cell carcinomas, further indicating a specific role for LTBP3 in cancer progression toward metastatic disease.

Project description:Background: Accumulating evidence indicates that aberrant activation of the Hedgehog (Hh) signalling pathway by Glioma-associated oncogene (Gli) transcription factors is involved in the aggressive progression of cancers, including ovarian cancer. Whereas the molecular mechanism underlying this phenomenon remains unelucidated. Matrix metalloproteinase-7 (MMP-7) facilitates degradation of the extracellular matrix, promoting the invasion of tumour cells, and is associated with cancer progression and metastasis. In previous reports, we identified a set of genes regulated by Hh signalling in ovarian tumour cells among which MMP-7 was identified as a potential Hh target gene candidate. However, establishing an association between Hh signalling activation and MMP-7 expression requires further validation, and the function of this regulation remains unknown. Methods: A cDNA microarray was utilized to identify potential downstream targets of Hh signalling. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate mRNA expression, and immunoblotting (IB) was conducted to evaluate protein expression. The invasive and migratory capabilities of tumour cells were tested with the transwell and wound healing assays, respectively. The mRNA levels of Gli2 and MMP-7 in normal ovarian tissues and cancerous tissues in various stages together with the corresponding clinical information were acquired from the indicated GEO datasets to elucidate associations between MMP-7 expression and cancer progression and prognosis. Additionally, immunohistochemistry (IHC) was performed in multiple ovarian cancers, benign tumours and normal tissues to evaluate Gli2 and MMP-7 protein expression. Results: MMP-7 expression was regulated by the Hh ligand, antagonist and downstream transcript factor Gli2, demonstrating this gene as an Hh target. MMP-7 facilitated the invasion and migration of ovarian tumour cells, indicating its key function in ovarian cancer progression. IHC analysis demonstrated abnormally increased Gli2 and MMP-7 expression levels in benign tumours and ovarian cancer tissues. Moreover, high MMP-7 levels were significantly associated with poor overall survival (OS) and poor progression-free survival (PFS) in ovarian cancer patients. Conclusion: Aberrant activation of the Hh-Gli-MMP-7 signalling axis is essential for acceleration of the progression and metastasis of human ovarian cancer, implicating its use as a novel therapeutic target of ovarian cancer. In addition, MMP-7 can potentially serve as a prognostic marker of ovarian cancer.

Dataset Information

Human Epididymis Protein 4 Promotes Events Associated with Metastatic Ovarian Cancer via Regulation of the Extracelluar Matrix.

Publications

Human Epididymis Protein 4 Promotes Events Associated with Metastatic Ovarian Cancer <i>via</i> Regulation of the Extracelluar Matrix.

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