Muratovska, A., Zhou, C., He, S., Goodyer, P. & Eccles, M. R. Paired-Box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene 22, 7989-7997

Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand.
Oncogene (Impact Factor: 8.46). 10/2003; 22(39):7989-97. DOI: 10.1038/sj.onc.1206766
Source: PubMed


The paired-box (PAX) genes encode a family of nine well-characterized paired-box transcription factors, with important roles in development and disease. Although PAX genes are primarily expressed in the embryo, constitutive expression promotes tissue hyperplasia. Rare tumor-specific mutations of PAX genes implicate an oncogenic role, and persistent PAX expression characterizes several tumors. Yet, a cancer-wide analysis of PAX gene expression to investigate a general role for PAX genes has not been performed. We analysed the pattern and requirement for PAX gene expression in a panel of common cancer cell lines. Very frequent PAX gene expression was identified in tumor cell lines, including lymphoma, breast, ovarian, lung, and colon cancer. In addition, the PAX2 gene was frequently expressed in a panel of 406 common primary tumor tissues. Apoptosis was rapidly induced in ovarian and bladder cancer cell lines following RNA interference to silence PAX2 expression, despite concomitant TP53 and/or HRAS mutations. These data suggest that PAX genes are frequently expressed in cancer, and that endogenous PAX gene expression is required for the growth and survival of cancer cells.

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    • "In most cases, PAX gene expression attenuates when development is complete, but in a few tissues, it persists into adult life. However, abnormal cell growth and proliferation is often associated with high expression levels of PAX genes [4]. Nevertheless, the precise role that PAX genes play in cancer is still unclear. "
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    ABSTRACT: PAX8 is a member of the paired box (Pax) multigene family of transcription factors, which are involved in the developmental and tissue-specific control of the expression of several genes in both vertebrates and invertebrates. Previously, several studies reported that PAX8 is expressed at high levels in specific types of tumors. In particular, PAX8 has been recently reported to be conspicuously expressed in human ovarian cancer, but the functional role of PAX8 in the carcinogenesis of this type of tumor has not been addressed. In this study, we investigated the contribution of PAX8 in ovarian cancer progression. Stable PAX8 depleted ovarian cancer cells were generated using short hairpin RNA (shRNA) constructs. PAX8 mRNA and protein were detected by RT-PCR, immunoblot and immunofluorescence. Cell proliferation, motility and invasion potential of PAX8 silenced cells were analyzed by means of growth curves, wound healing and Matrigel assays. In addition, PAX8 knockdown and control cells were injected into nude mice for xenograft tumorigenicity assays. Finally, qPCR was used to detect the expression levels of EMT markers in PAX8-overexpressing and control cells. Here, we show that PAX8 plays a critical role in the migration, invasion and tumorigenic ability of ovarian cancer cells. Our results show that RNA interference-mediated knockdown of PAX8 expression in SKOV-3 ovarian cancer cells produces a significant reduction of cell proliferation, migration ability and invasion activity compared with control parental SKOV-3 cells. Moreover, PAX8 silencing strongly suppresses anchorage-independent growth in vitro. Notably, tumorigenesis in vivo in a nude mouse xenograft model is also significantly inhibited. Overall, our results indicate that PAX8 plays an important role in the tumorigenic phenotype of ovarian cancer cells and identifies PAX8 as a potential new target for the treatment of ovarian cancer.
    BMC Cancer 04/2014; 14(1):292. DOI:10.1186/1471-2407-14-292 · 3.36 Impact Factor
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    • "We and others showed that both MET and RON provide essential growth signals for lung tumor development and also play a key role in metastasis [4]. It is not surprising that PAX8 knockdown results in significant loss in A549 cell viability; as such a role was demonstrated for PAX transcription factors including PAX8 in the promotion of cancer cell growth [12,24,25]. In order to rule out the vagaries of using one transformed cell line, A549, we also repeated the functional assays using H1993, another NSCLC cell line and investigated the effects of PAX 8 knockdown on loss of cell motility and viability. "
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    ABSTRACT: Non-small cell lung cancers (NSCLC) are highly heterogeneous at the molecular level and comprise 75% of all lung tumors. We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis. Subsequent studies from our lab also revealed that PAX5 transcription factor is preferentially expressed in small cell lung cancer (SCLC) and promotes MET transcription. PAX8, however, is also expressed in NSCLC cell lines. We therefore investigated the role of PAX8 in NSCLC. Using IHC analysis, PAX8 protein expression was determined in archival NSCLC tumor tissues (n = 254). In order to study the effects of PAX8 knockdown on NSCLC cellular functions such as apoptosis and motility, siRNA against PAX8 was used. Confocal fluorescence microscopy was used to monitor the localization of MET, RON and PAX8. The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay. Relative levels of PAX8 protein were elevated (>= + 2 on a scale of 0-3) in adenocarcinoma (58/94), large cell carcinoma (50/85), squamous cell carcinoma (28/47), and metastatic NSCLC (17/28; lymph node). Utilizing early progenitors isolated from NSCLC cell lines and fresh tumor tissues, we observed robust overexpression of PAX8, MET, and RON. PAX8 knockdown A549 cells revealed abrogated PAX8 expression with a concomitant loss in MET and the related RON kinase expression. A dramatic colocalization between the active form of MET (also RON) and PAX8 upon challenging A549 cells with HGF was visualized. A similar colocalization of MET and EGL5 (PAX8 ortholog) proteins was found in embryos of C. elegans. Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~ 6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target. However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU11274, had marginal additive effect on loss of NSCLC cell viability. PAX8 provides signals for growth and motility of NSCLC cells and is necessary for MET and RON expression. Further investigations are necessary to investigate the therapeutic potential of PA8 in NSCLC.
    BMC Cancer 03/2014; 14(1):185. DOI:10.1186/1471-2407-14-185 · 3.36 Impact Factor
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    • "PAX8 is expressed at the midbrain-hindbrain junction during brain development and is virtually absent in the adult brain [16]. In earlier studies involving PAX8 and glioblastomas, we found increased PAX8 expression in tumours using a small panel of 14 telomerase-positive tumours and cell lines [14,17]. The tumour-promoting functions of PAX8 include the ability to transform cells and to form tumours in mice [18], an increased telomerase activity [17], and the promotion of cell cycle progression [19]. "
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    ABSTRACT: The molecular basis to overcome therapeutic resistance to treat glioblastoma remains unclear. The anti-apoptotic b cell lymphoma 2 (BCL2) gene is associated with treatment resistance, and is transactivated by the paired box transcription factor 8 (PAX8). In earlier studies, we demonstrated that increased PAX8 expression in glioma cell lines was associated with the expression of telomerase. In this current study, we more extensively explored a role for PAX8 in gliomagenesis METHODS: PAX8 expression was measured in 156 gliomas including telomerase-negative tumours, those with the alternative lengthening of telomeres (ALT) mechanism or with a non-defined telomere maintenance mechanism (NDTMM), using immunohistochemistry and quantitative PCR. We also tested the affect of PAX8 knockdown using siRNA in cell lines on cell survival and BCL2 expression RESULTS: Seventy-two percent of glioblastomas were PAX8-positive (80% telomerase, 73% NDTMM, and 44% ALT). The majority of the low-grade gliomas and normal brain cells were PAX8-negative. The suppression of PAX8 was associated with a reduction in both cell growth and BCL2, suggesting that a reduction in PAX8 expression would sensitise tumours to cell death. PAX8 is increased in the majority of glioblastomas and promoted cell survival. Because PAX8 is absent in normal brain tissue, it may be a promising therapeutic target pathway for treating aggressive gliomas.
    BMC Cancer 03/2014; 14(1):159. DOI:10.1186/1471-2407-14-159 · 3.36 Impact Factor
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