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HE4 (WFDC2) Promotes Tumor Growth in Endometrial Cancer Cell Lines.

ABSTRACT: HE4, also known as WFDC2, is a useful biomarker for ovarian cancer when either used alone or in combination with CA125. HE4 is also overexpressed in endometrial cancer (EC), but its function in cancer cells is not clear. In this study, we investigate the role of HE4 in EC progression. An HE4-overexpression system was established by cloning the HE4 prototypic mRNA variant (HE4-V0) into a eukaryotic expression vector. Following transfection, stable clones in two EC cell lines were selected. The effects of HE4 overexpression on cell growth and function were measured with the use of cell proliferation assay, matrigel invasion, and soft agar gel colony formation assays. HE4-induced cancer cell proliferation in vivo was examined in a mouse xenograft model. HE4 overexpression significantly enhanced EC cell proliferation, matrigel invasion, and colony formation in soft agar. Moreover, HE4 overexpression promoted tumor growth in the mouse xenograft model. HE4 overexpression enhanced several malignant phenotypes in cell culture and in a mouse model. These results are consistent with our previous observation that high levels of serum HE4 closely correlate with the stage, myometrial invasion and tumor size in patients with EC. This study provides evidence that HE4 overexpression directly impacts tumor progression in endometrial cancer.

SUBMITTER: Li J

PROVIDER: S-EPMC3634435 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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HE4 (WFDC2) Promotes Tumor Growth in Endometrial Cancer Cell Lines.

Li Jinping J Chen Haibin H Mariani Andrea A Chen Dong D Klatt Edward E Podratz Karl K Drapkin Ronny R Broaddus Russell R Dowdy Sean S Jiang Shi-Wen SW

International journal of molecular sciences 20130315 3

HE4, also known as WFDC2, is a useful biomarker for ovarian cancer when either used alone or in combination with CA125. HE4 is also overexpressed in endometrial cancer (EC), but its function in cancer cells is not clear. In this study, we investigate the role of HE4 in EC progression. An HE4-overexpression system was established by cloning the HE4 prototypic mRNA variant (HE4-V0) into a eukaryotic expression vector. Following transfection, stable clones in two EC cell lines were selected. The ef ...[more]

PMID: 23502467

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Project description:The platelet-derived growth factor-D (PDGF-D) was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human endometrial cancer. Alterations of PDGF-D mRNA and protein were determined by real time PCR, western blot and immunohistochemical staining. Up-regulation of PDGF-D was achieved by stably transfecting the pcDNA3-PDGF-D plasmids into ECC-1 cells; and knockdown of PDGF-D was achieved by transient transfection with siRNA-PDGF-D into Ishikawa cells. The MTT assay, colony formation assay and Transwell assay were used to detect the effects of PDGF-D on cellular proliferation and invasion. The xenograft assay was used to investigate the functions of PDGF-D in vivo. Compared to normal endometrium, more than 50% cancer samples showed over-expression of PDGF-D (p < 0.001), and high level of PDGF-D was correlated with late stage (p = 0.003), deep myometrium invasion (p < 0.001) and lympha vascular space invasion (p = 0.006). In vitro, over-expressing PDGF-D in ECC-1 cells significantly accelerated tumor growth and promoted cellular invasion by increasing the level of MMP2 and MMP9; while silencing PDGF-D in Ishikawa cells impaired cell proliferation and inhibited the invasion, through suppressing the expression of MMP2 and MMP9. Moreover, we also demonstrated that over-expressed PDGF-D could induce EMT and knockdown of PDGF-D blocked the EMT transition. Consistently, in xenografts assay, PDGF-D over-expression significantly promoted tumor growth and tumor weights. We demonstrated that PDGF-D was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion. Both in vitro and in vivo experiments showed PDGF-D could promote tumor growth and invasion through up-regulating MMP2/9 and inducing EMT. Thus, we propose targeting PDGF-D to be a potent strategy for endometrial cancer treatment.

Project description:Introduction: Amplification at chromosome 8q24 is one of the most frequent genomic abnormalities in human cancers and is associated with reduced survival duration in breast and ovarian cancers. The minimal amplified region encodes c-MYC and the non-coding RNA, PVT1 including miR-1204 encoded in exon 1b. Here we analyzed the genomic changes at chromosome 8q24.21 in breast cancer and the functional roles of miR-1204 in breast and ovarian cancer progression. Methods: The genomic changes at chromosome 8q24.21 were detected in 997 breast cancer tumors and 40 breast cancer cell lines. Expression of miR-1204 in breast and ovarian cancer cell lines was investigated by qRT-PCR method. The role of miR-1204 in the tumorigenesis of breast and ovarian cancer was explored using both knockdown and overexpression of miR-1204 in vitro. Candidate miR-1204 target genes from two independent expression microarray datasets and computational predict programs were identified and further validated by qRT-PCR and western blot methods. The role of inhibition of miR-1204 on tamoxifen sensitivity in breast cancer cells was also investigated. Results: MiR-1204 is frequently co-amplified with MYC and expression of miR-1204 is strongly correlated with the expression and amplification of the noncoding PVT1 transcript and less so with MYC in human breast and ovarian cancer cells. Inhibition of miR-1204 decreases cell proliferation and increased apoptosis in breast and ovarian cancer cell lines with 8q24 amplification, but not in lines without amplification and so may be involved in Myc-induced apoptosis. Additionally, overexpression of miR-1204 enhances both breast and ovarian cancer cell growth and Myc-initiated Rat1A cell transformation. Computational and experimental analyses 30 promising candidate miR-1204 target genes. mRNA levels for these genes were assessed after over expression and knockdown of miR-1204 as were protein levels for 10 genes for which antibodies were available. These studies implicated VDR and ESR1 as miR-1204 targets. Inhibition of miR-1204 increased response to tamoxifen in Estrogen Receptor negative breast cancer cell lines. Conclusions: We conclude that amplification of miR-1204 contributes to breast and ovarian pathophysiology at least in part, by increasing proliferation and down regulating apoptosis and by decreasing expression of VDR and ESR1. Seven cell line sample pairs, where samples are LNA transfected with antimiR-1204 or antimiR-1204 control

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HE4 (WFDC2) Promotes Tumor Growth in Endometrial Cancer Cell Lines.

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HE4 (WFDC2) Promotes Tumor Growth in Endometrial Cancer Cell Lines.

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