Aspartyl-asparagyl β hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms

Cantarini, Maria Chiara; Monte, Suzanne M. de la; Pang, Maoyin; Tong, Ming; D’Errico, Antonietta; Trevisani, Franco; Wands, Jack R.

doi:10.1002/hep.21272

Cited by 151 publications

(244 citation statements)

References 52 publications

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“…If CCBE1 activity is modulated by hydroxylation of Asp/Asn residues by BAH, it could be predicted that silencing of CCBE1 may result in a similar tumourpromoting effect to that of BAH loss, although this remains to be determined. However, over-expression of BAH/AAH has been reported in a number of carcinomas (Lavaissiere et al, 1996;Cantarini et al, 2006) in which it mediates increased cellular motility/migration and invasion through hydroxylation of proteins containing the Asp/Asn consensus site (Engel, 1989;Gronke et al, 1989;Lieber et al, 1992;Monkovic et al, 1992;Sepe et al, 2002;Maeda et al, 2003;de la Monte et al, 2006), which is linked to cellular transformation (Ince et al, 2000). Relative expression levels of BAH in ovarian carcinomas have yet to be reported.…”

Section: Discussionmentioning

confidence: 99%

Collagen and calcium-binding EGF domains 1 is frequently inactivated in ovarian cancer by aberrant promoter hypermethylation and modulates cell migration and survival

Barton

Gloss

et al. 2009

Br J Cancer

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BACKGROUND: Collagen and calcium-binding EGF domains 1 (CCBE1) is an uncharacterised gene that has down-regulated expression in breast cancer. As CCBE1 maps to 18q21.32, a region frequently exhibiting loss of heterozygosity in ovarian cancer, the aim of this study was to determine the expression and function of CCBE1 in ovarian cancer. METHODS: Expression and methylation patterns of CCBE1 were determined in ovarian cancer cell lines and primary tumours. CCBE1 contains collagen repeats and an aspartic acid/asparagine hydroxylation/EGF-like domain, suggesting a function in extracellular matrix remodelling and migration, which was determined using small-interfering RNA (siRNA)-mediated knockdown and over-expression of CCBE1 in cell lines. RESULTS: CCBE1 is expressed in normal ovary, but is reduced in ovarian cancer cell lines and primary carcinomas. Pharmacological demethylation/deacetylation in ovarian cancer cell lines re-induced CCBE1 expression, indicating that epigenetic mechanisms contribute to its silencing in cancer. CCBE1 promoter hypermethylation was detected in 6/11 (55%) ovarian cancer cell lines and 38/ 81 (41%) ovarian carcinomas. siRNA-mediated knockdown of CCBE1 in ovarian cancer cell lines enhanced their migration; conversely, re-expression of CCBE1 reduced migration and survival. Hence, loss of CCBE1 expression may promote ovarian carcinogenesis by enhancing migration and cell survival. CONCLUSIONS: These data suggest that CCBE1 is a new candidate tumour suppressor in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Collagen and calcium-binding EGF domains 1 is frequently inactivated in ovarian cancer by aberrant promoter hypermethylation and modulates cell migration and survival

Barton

Gloss

et al. 2009

Br J Cancer

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“…? IGF-IR [53] ? IRS-1 [63] Tumor growth Invasion Metastases www.wjgnet.com Breuhahn K et al IGF-Ⅱ signaling in HCC signaling in HCC predominantly occurs at the level of IGF-Ⅱ expression, which is secreted by the tumor cells themselves, which is suggestive of autocrine mechanisms of stimulation [26,27] .…”

Section: Igf-signaling In Hepatocarcinoge-nesismentioning

confidence: 99%

“…However, other studies did not detect any genetic alterations at the igf-Ⅱr locus, which may be due to methodological and population-based differences [50][51][52] . Moreover, few studies described elevated IGF-ⅡR levels in HCCs [53,54] . Independent of the underlying molecular mechanism, IGF-Ⅱ overexpression denominates a group of HCCs with fewer tumor infiltrating lymphocytes, a lower apoptosis rate [55] and extrahepatic metastasis [56] .…”

Section: Igf-signaling In Hepatocarcinoge-nesismentioning

confidence: 99%

“…The pivotal oncogenic function of IGF-Ⅱ-signaling IGF-II 9.2 [117] 22.5 [26] 25.6-60 [118] 66.7 [54] 40 [119] 100 [120] 50 [121] 14 [55] IGF-IR 7-78 [117] 40 [53] IRS-1 46.7 [53] 100 [122] IRS-2 53.3 [53] 86 [123] IRS-4 46.7 [53] in hepatocarcinogenesis is supported by several animal models. Transgenic mice expressing IGF-Ⅱ (20-30-fold increased levels in serum) develop hypoglycemia and many types of malignancies, which are most frequently HCC [67] .…”

Section: Animal Modelsmentioning

confidence: 99%

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Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Breuhahn¹

2008

WJG

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“…Overexpression of IRS1 or -2 induces tumorigenesis of the mammary gland (Dearth et al 2006) and IRS2 expression promotes metastasis (Jackson et al 2001, Nagle et al 2004 underlining the importance of IRS2 expression for human diseases. Furthermore, 80% of human hepatocellular carcinomas overexpress IRS2, suggesting a major role for IRS2 in liver carcinogenesis and tumor growth (Boissan et al 2005, Cantarini et al 2006. During liver regeneration after partial hepatectomy IRS2 expression increases time-dependently (Escribano et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells

Udelhoven¹,

Leeser²,

Freude³

et al. 2009

Journal of Molecular Endocrinology

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Recent studies have discovered changes in the insulin-/IGF1 signaling affecting glucose metabolism and the molecular pathogenesis of human hepatocellular cancer. Insulin/IGF1 receptor mediates its intracellular effects by recruitment of one out of the four different insulin receptor substrates (IRS). To investigate mechanisms of IRS2 expression, we analyzed transcriptional regulation of IRS2 in human HepG2 cells. We identified a region 688 bp upstream of the translation start codon responsible for w90% of basal human IRS2 promoter activity in HepG2 cells, and confirmed binding of specificity protein 1 (also called Sp1 transcription factor, SP1) and nuclear factor 1 (NFI) in this region. Mutation of both SP1 and NFI binding sites or inhibition of extracellular signal regulated kinase (ERK) suppressed IRS2 promoter activity almost completely, revealing a major role of MAP kinases (MAPK) for IRS2 transcription. Activating this cascade with oxidative stress increased IRS2 promoter activity and endogenous IRS2 expression substantially. IRS2 promoter activity rose even more after additional inhibition of p38MAPK indicating an inhibitory effect of p38MAPK on ERK mediated IRS2 transcription. Activation of the MAPK pathway using interleukin 1, beta (IL1B) increased IRS2 promoter activity similar to oxidative stress. In contrast IL1B decreases and inhibition of the MAPK pathway increases IRS1 promoter activity revealing opposed effects of IL1B and ERK on the expression of different IRS proteins. In conclusion we discovered a specific region (K688 to K611 bp) in the IRS2 promoter essential for basal promoter activity and oxidative stress induced transcription depending on ERK activation and SP1 and NFI binding in human hepatocytes.

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Aspartyl-asparagyl β hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms

Abstract: Aspartyl-(Asparagyl)-␤-hydroxylase (AAH) is overexpressed in various malignant neoplasms, including hepatocellular carcinomas (HCCs

Cited by 151 publications

References 52 publications

Collagen and calcium-binding EGF domains 1 is frequently inactivated in ovarian cancer by aberrant promoter hypermethylation and modulates cell migration and survival

Collagen and calcium-binding EGF domains 1 is frequently inactivated in ovarian cancer by aberrant promoter hypermethylation and modulates cell migration and survival

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells

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