Gene expression changes during HPV‐mediated carcinogenesis: A comparison between an <i>in vitro</i> cell model and cervical cancer

Wan, Fang; Miao, Xijiang; Quraishi, Iram; Kennedy, Valerie; Creek, Kim E.; Pirisi, Lucia

doi:10.1002/ijc.23463

Cited by 79 publications

(104 citation statements)

References 49 publications

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“…Overexpression of SIX1 is observed in various types of cancer such as hepatocellular carcinoma (Ng et al, 2006), breast cancer (Kumar, 2009), ovarian cancer (Behbakht et al, 2007) and cervical cancer (Wan et al, 2008). In addition, overexpression of SIX1 is likely to be related to progression, invasion or metastasis in some cancers such as hepatocellular carcinoma (Ng et al, 2006) and breast cancer (Coletta et al, 2008), although understanding of the molecular mechanisms of SIX1 Figure 4 (a) ZEB1 and SNAI1 mRNA (left, bar graphs) and protein (right, western blotting) expression level in SIX1-introduced SW480 cells compared with their empty vector-transfected counterparts.…”

Section: Discussionmentioning

confidence: 99%

“…Through quantitative reverse transcription-PCR (RT-PCR) analysis, the results of our microarray-based analyses were validated in 11 genes (Supplementary Table S3). Based on these results, we focused on the SIX1 gene, because (a) SIX1 is known to be a transcriptional factor designating as a homeoprotein and essential for development of organs (Zheng et al, 2003;Kumar, 2009); and (b) altered expression of this gene is observed in various cancers (Ford et al, 1998;Ng et al, 2006;Behbakht et al, 2007;Coletta et al, 2008;Wan et al, 2008) and induces EMT in mammary cells (Micalizzi et al, 2009). Subsequent quantitative RT-PCR analysis of a panel of CRC cell lines showed that SIX1 mRNA expression is frequently positive (8/18 lines, 44%; Figure 1c).…”

Section: Six1 Gene Is a Putative Mesenchymal Marker In Crc Cellsmentioning

confidence: 99%

“…In immunohistochemical analysis of primary CRC cases, we then focused on the invasive front, where ZEB1 is known to be dominantly expressed in human CRC cells (Wan et al, 2008). SIX1 was expressed in both differentiated cells, which were the major component of the primary CRC tumor, and dedifferentiated cancer cells at the invasive front in CRC.…”

Section: Characteristics Of Six1 Overexpression In Primary Tumors Of mentioning

confidence: 99%

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SIX1 promotes epithelial–mesenchymal transition in colorectal cancer through ZEB1 activation

et al. 2012

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Epithelial-mesenchymal transition (EMT) has a major role in cancer progression, as well as normal organ development and human pathology such as organ fibrosis and wound healing. Here, we performed a gene expression array specialized in EMT of colorectal cancer (CRC). From a comprehensive gene expression analysis using epithelial-and mesenchymal-like CRC cell lines, and following the ontology (GO) analysis, SIX1 gene was identified to be an EMT-related gene in CRC. Using SW480 cells stably transfected with a SIX1 expression construct and their control counterparts, we demonstrated that SIX1 overexpression represses CDH1 expression and promotes EMT in CRC. SIX1-induced CDH1 repression and EMT in CRC cells were correlated at least in part with posttranscriptional ZEB1 activation and miR-200-family transcriptional repression. In primary tumors of CRC, in accord with the functional findings, aberrant expression of SIX1 in cancer cells was observed at the disruption of the basement membrane and at the tumor invasive front, where tumor cells underwent EMT in vivo. Taken together, SIX1 overexpression is suggested to occur in carcinogenesis, and contribute to repression of CDH1 expression and promotion of EMT partly through repression of miR-200-family expression and activation of ZEB1 in CRC.

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Section: Discussionmentioning

confidence: 99%

Section: Six1 Gene Is a Putative Mesenchymal Marker In Crc Cellsmentioning

confidence: 99%

Section: Characteristics Of Six1 Overexpression In Primary Tumors Of mentioning

confidence: 99%

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SIX1 promotes epithelial–mesenchymal transition in colorectal cancer through ZEB1 activation

et al. 2012

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“…HKc/HPV16 represent freshly immortalized cells, whereas HKc/DR have been selected for resistance to differentiation and failure to growth arrest in response to TGF-ß (13). Whereas both cell lines are nontumorigenic, mRNA expression analysis has shown that HKc/DR are more similar to cervical carcinoma cells than HKc/HPV16 cells (14). As in our experiments with cervical cancer lines, we designated kinases as "essential candidates" when their depletion yielded ≥50% difference in proliferation/survival relative to HFKs.…”

Section: Identification Of Human Kinases That Become Important At Dismentioning

confidence: 99%

Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3

Baldwin

Grueneberg

Hellner

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Cervical carcinomas are initiated through a series of well-defined stages that rely on the expression of human papillomavirus (HPV) oncogenes. A panel of 100 small hairpin RNAs that target essential kinases in many tumor types was used to study the stepwise appearance of kinase requirements during cervical tumor development. Twenty-six kinases were commonly required in three cell lines derived from frank carcinomas, and each kinase requirement was traced to the specific stage in which the requirement emerged. Six kinases became required following HPV-induced immortalization, and the requirement for two kinases, SGK2 and PAK3, was mapped to the inactivation of p53 in primary human epithelial cells. Loss of the p53 tumor suppressor in other primary epithelial cells also induced dependence on SGK2 and PAK3. Hence, SGK2 and PAK3 provide important cellular functions following p53 inactivation, fulfilling the classical definition of synthetic lethality; loss of p53, SGK2, or PAK3 alone has little effect on cell viability, whereas loss of p53 together with either SGK2 or PAK3 loss leads to cell death. Whereas tumor suppressor gene mutations are not directly druggable, other proteins or pathways that become obligatory to cell viability following tumor suppressor loss provide theoretical targets for tumor suppressor-specific drug discovery efforts. The kinases SGK2 and PAK3 may thus represent such targets for p53-specific drug development.shRNA | screening | E6 oncoprotein | cancer | viral oncogenesis

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“…One homeobox gene of interest is the Six1 homeoprotein, which has an important role in the expansion of progenitor cell populations during early embryogenesis (Grifone et al, 2005) and is known to be essential for the development of numerous organs (Li et al, 2003;Zheng et al, 2003;Ozaki et al, 2004). In addition, Six1 is reported to be overexpressed in multiple pediatric and adult human cancers, including breast (Ford et al, 1998), ovarian (Behbakht et al, 2007), cervical (Wan et al, 2008) and hepatocellular carcinomas (Ng et al, 2006), as well as rhabdomyosarcomas and Wilms' tumors (Li et al, 2002;Yu et al, 2004). It is important to note that Six1 overexpression has been strongly associated with aggressive, metastatic cancers and poor prognosis (Coletta et al, 2004;Yu et al, 2004;Behbakht et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers

et al. 2010

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Homeobox genes encode transcription factors that are essential for normal development and are often dysregulated in cancers. The molecular mechanisms that cause their misregulation in cancers are largely unknown. In this study, we investigate the mechanism by which the Six1 homeobox protein, which has a crucial role during development, is frequently deregulated in several poor outcome, aggressive, metastatic adult human cancers, including breast cancer, ovarian cancer, hepatocellular carcinoma and pediatric malignancies such as rhabdomyosarcoma and Wilms' tumor. Our results reveal that miRNA-185 translationally represses Six1 by binding to its 3 0 -untranslated region. Analyses of ovarian cancers, pediatric renal tumors and multiple breast cancer cell lines showed decreased miR-185 expression, paralleling an increase in Six1 levels. Further investigation revealed that miR-185 impedes anchorage-independent growth and cell migration, in addition to suppressing tumor growth in vivo, implicating it to be a potent tumor suppressor. Our results indicate that miR-185 mediates its tumor suppressor function by regulating cell-cycle proteins and Six1 transcriptional targets c-myc and cyclin A1. Furthermore, we show that miR-185 sensitizes Six1-overexpressing resistant cancer cells to apoptosis in general and tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-mediated apoptosis in particular. Together, our findings suggest that the altered expression of the novel tumor suppressor miR-185 may be one of the central events that leads to dysregulation of oncogenic protein Six1 in human cancers.

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Gene expression changes during HPV‐mediated carcinogenesis: A comparison between an in vitro cell model and cervical cancer

Cited by 79 publications

References 49 publications

SIX1 promotes epithelial–mesenchymal transition in colorectal cancer through ZEB1 activation

SIX1 promotes epithelial–mesenchymal transition in colorectal cancer through ZEB1 activation

Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3

MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers

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