HTPAP gene on chromosome 8p is a candidate metastasis suppressor for human hepatocellular carcinoma

Wu, Xiaoyun; Hl, Jia; Wang, Yafang; Ren, Ning; Qh, Ye; Sun, Hui‐Chuan; Wang, L; Yk, Liu; Zy, Tang; Lx, Qin

doi:10.1038/sj.onc.1209191

Cited by 32 publications

(29 citation statements)

References 36 publications

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“…The only published report on PPAPDC1B suggests, based on the down-regulation of this gene in metastatic human hepatocellular carcinoma (HCC) and on experimental criteria, that it may act as a metastasis suppressor in HCC (40). In contrast, its overexpression in a subset of breast cancers due to gene amplification, together with the experimental data reported here, indicates that it may have an opposite, oncogenic role in a different cell background.…”

Section: Discussionmentioning

confidence: 38%

Characterization of the Recurrent 8p11-12 Amplicon Identifies PPAPDC1B, a Phosphatase Protein, as a New Therapeutic Target in Breast Cancer

et al. 2008

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The 8p11-12 chromosome region is one of the regions most frequently amplified in breast carcinoma (10-15% of cases). Several genes within this region have been identified as candidate oncogenes, as they are both amplified and overexpressed. However, very few studies have explored the role of these genes in cell transformation, with the aim of identifying valuable therapeutic targets. An analysis of comparative genomic hybridization array and expression profiling data for a series of 152 ductal breast carcinomas and 21 cell lines identified five genes (LSM1, BAG4, DDHD2, PPAPDC1B, and WHSC1L1) within the amplified region as consistently overexpressed due to an increased gene copy number. The use of small interfering RNA to knock down the expression of each of these genes showed the major role played by two genes, PPAPDC1B and WHSC1L1, in regulating the survival and transformation of two different cell lines harboring the 8p amplicon. The role of these two genes in cell survival and cell transformation was also confirmed by long-term knockdown expression studies using short hairpin RNAs. The potential of PPAPDC1B, which encodes a transmembrane phosphatase, as a therapeutic target was further shown by the strong inhibition of growth of breast tumor xenografts displaying 8p11-12 amplification induced by the silencing of PPAPDC1B. The oncogenic properties of PPAPDC1B were further shown by its ability to transform NIH-3T3 fibroblasts, inducing their anchorage-independent growth. Finally, microarray experiments on PPAPDC1B knockdown indicated that this gene interfered with multiple cell signaling pathways, including the Janus-activated kinase-signal transducer and activator of transcription, mitogen-activated protein kinase, and protein kinase C pathways. PPAPDC1B may also potentiate the estrogen receptor pathway by downregulating DUSP22. [Cancer Res 2008;68(17):7165-75]

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Section: Discussionmentioning

confidence: 38%

Characterization of the Recurrent 8p11-12 Amplicon Identifies PPAPDC1B, a Phosphatase Protein, as a New Therapeutic Target in Breast Cancer

et al. 2008

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“…In addition, RAB11FIP1 and PPAPDC1B, which have been consistently implicated as candidate oncogenes based on their statistical association between amplification and expression and their biological function, had no transforming activity in our biological assays. Interestingly, PPAPDC1B has been recently implicated as a possible metastasis suppressor in hepatocellular carcinoma by showing that PPAPDC1B overexpression decreased invasion and metastasis with no effect on growth of the primary tumor (56).…”

Section: Discussionmentioning

confidence: 99%

Multiple Interacting Oncogenes on the 8p11-p12 Amplicon in Human Breast Cancer

Yang¹,

Streicher²,

et al. 2006

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The 8p11-p12 genomic region is amplified in 15% of breast cancers and harbors several candidate oncogenes. However, functional evidence for a transforming role for these genes is lacking. We identified 21 genes from this region as potential oncogenes based on statistical association between copy number and expression. We further showed that three of these genes (LSM1, BAG4, and C8orf4) induce transformed phenotypes when overexpressed in MCF-10A cells, and overexpression of these genes in combination influences the growth factor independence phenotype and the ability of the cells to grow under anchorage-independent conditions. Thus, LSM1, BAG4, and C8orf4 are breast cancer oncogenes that can work in combination to influence the transformed phenotype in human mammary epithelial cells. (Cancer Res 2006; 66(24): 11632-43)

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“…UNC5D is mapped to chromosome 8p12. This region is frequently aberrant in many cancers (41) and may harbor some candidate tumor suppressor genes, such as SFRP1 (42), HTPAP (43), and a breast cancer susceptibility gene (44). UNC5D itself is also included in the homozygously deleted region at D8S87 in prostate cancer (45), in the region with some recurrent breaks in breast cancer (46), and in the deleted region in muscle-invasive bladder cancer (47).…”

Section: Discussionmentioning

confidence: 99%

Dependence receptor UNC5D mediates nerve growth factor depletion–induced neuroblastoma regression

Zhu¹,

Li²,

Haraguchi³

et al. 2013

J. Clin. Invest.

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Spontaneous regression of neuroblastoma (NB) resembles the developmentally regulated programmed cell death (PCD) of sympathetic neurons. Regressing tumor cells express high levels of the nerve growth factor (NGF) receptors TRKA and p75 NTR and are dependent on NGF for survival; however, the underlying molecular mechanism remains elusive. Here, we show that UNC5D, a dependence receptor that is directly targeted by p53 family members, is highly expressed in favorable NBs. NGF withdrawal strongly upregulated UNC5D, E2F1, and p53 in human primary favorable NBs. The induced UNC5D was cleaved by caspases 2/3, and the released intracellular fragment translocated into the nucleus and interacted with E2F1 to selectively transactivate the proapoptotic target gene. The cleavage of UNC5D and its induction of apoptosis were strongly inhibited by addition of netrin-1. Unc5d -/-mice consistently exhibited a significant increase in dorsal root ganglia neurons and resistance to NGF depletion-induced apoptosis in sympathetic neurons compared with wild-type cells. Our data suggest that UNC5D forms a positive feedback loop with p53 and E2F1 to promote NGF dependencemediated PCD during NB regression.

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HTPAP gene on chromosome 8p is a candidate metastasis suppressor for human hepatocellular carcinoma

Cited by 32 publications

References 36 publications

Characterization of the Recurrent 8p11-12 Amplicon Identifies PPAPDC1B, a Phosphatase Protein, as a New Therapeutic Target in Breast Cancer

Characterization of the Recurrent 8p11-12 Amplicon Identifies PPAPDC1B, a Phosphatase Protein, as a New Therapeutic Target in Breast Cancer

Multiple Interacting Oncogenes on the 8p11-p12 Amplicon in Human Breast Cancer

Dependence receptor UNC5D mediates nerve growth factor depletion–induced neuroblastoma regression

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