Frequent loss of imprinting of <i>IGF2</i> and <i>MEST</i> in lung adenocarcinoma

Kohda, Masakazu; Hoshiya, Hidetoshi; Katoh, Motonobu; Tanaka, Isao; Masuda, Ryosuke; Takemura, Tamiko; Fujiwara, Mutsunori; Oshimura, Mitsuo

doi:10.1002/mc.1053

Cited by 91 publications

(70 citation statements)

References 46 publications

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“…Interestingly, we observed that LOI/LOH of H19DMR not only was associated with higher IGF2 levels, but significantly correlated with overexpression of MEST and NNAT, which play an important role in fetal development (20)(21)(22)(23). Similar findings were published by Kohda et al who described a correlation of LOI at the IGF2/H19 locus and the MEST locus in case of lung adenocarcinomas (23).…”

Section: ------------------------------------------------------------supporting

confidence: 90%

“…Similar findings were published by Kohda et al who described a correlation of LOI at the IGF2/H19 locus and the MEST locus in case of lung adenocarcinomas (23). Thus, it might be …”

Section: ------------------------------------------------------------supporting

confidence: 88%

“…NNAT, IGF2, and MEST are involved in development and growth (20)(21)(22)(23), whereas the non-coding RNA of H19 and MEG3 exert regulatory function on the adjacent imprinting clusters (24,25). DLK1 and RTL1 are responsible for neuroendocrine differentiation and development of the placenta (15,20,21).…”

Section: Expression Of Imprinted Genes In Wilms Tumormentioning

confidence: 99%

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Altered expression of imprinted genes in Wilms tumors

Hubertus

Lacher²,

Rottenkolber³

et al. 2011

Oncol Rep

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Abstract. Overexpression of insulin-like growth factor 2 (IGF2), an imprinted gene located on chromosome 11p15, has been reported as a characteristic feature in various embryonal tumors, including Wilms tumor (WT). Recent studies specified loss of imprinting (LOI) in a differential methylated region (DMR) of the IGF2/H19 cluster or loss of heterozygosity (LOH), respectively, uniparental disomy (UPD) being responsible for this overexpression. However, the role of other imprinted genes in the genesis of WT is still unknown. In the current study, we analyzed transcriptional activity of the imprinted genes IGF2, H19, NNAT, DLK1, RTL1, MEG3, and MEST as well as the methylation status of the DMR of the IGF2/H19 cluster in a panel of 32 WTs. Except for H19, we detected massive overexpression of all genes in the majority of WTs compared to normal renal tissue, which was most prominent for the paternally expressed genes IGF2, NNAT, and MEST. Alterations of the H19DMR were found in two-thirds of the WTs. Moreover, we have seen a strong correlation between the transcriptional activity of IGF2, NNAT and MEST and LOI/LOH of H19DMR, which was inverse for H19. Expression of DLK1, RTL1 and MEG3 does not correlate with LOI/LOH of H19DMR. Altogether, our findings suggest that over-expression of imprinted genes is common in WTs and correlates at least for some imprinted genes with LOI of H19DMR. Thus, it may be speculated that alterations of the DNA modification machinery drive erroneous setting of methylation marks in imprinting regions throughout the genome, which leads to the concomitant activation of imprinted genes in blastomagenesis.

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Section: ------------------------------------------------------------supporting

confidence: 90%

“…Similar findings were published by Kohda et al who described a correlation of LOI at the IGF2/H19 locus and the MEST locus in case of lung adenocarcinomas (23). Thus, it might be …”

Section: ------------------------------------------------------------supporting

confidence: 88%

See 1 more Smart Citation

Altered expression of imprinted genes in Wilms tumors

Hubertus

Lacher²,

Rottenkolber³

et al. 2011

Oncol Rep

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“…IGF2 expression is from the paternal allele, whereas the maternal allele is normally inactive. IGF2 imprinting is relaxed in many different types of tumors, including osteosarcoma (7), lung adenocarcinomas (8), head and neck squamous cell adenocarcinomas (9,10), Wilms' tumor (11), prostate cancer (12), and colorectal carcinomas (13)(14)(15)(16)(17). This loss of imprinting (LOI) occurs when there is abnormal activation of the maternal copy of IGF2 and the resultant overexpression contributes to tumor growth.…”

Section: Introductionmentioning

confidence: 99%

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Murphy

Huang

Wen

et al. 2006

Molecular Cancer Research

127

103

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Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner. (Mol Cancer Res 2006;4(4):283 -92)

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“…Exogenous IGF-1 as a growth factor may also promote the growth of the tumor cells. IGF-1 combines with its receptors to activate the PI3K/Akt and MAPK signaling pathways (10), inhibiting tumor cell apoptosis and promoting cell proliferation, respectively (11)(12)(13)(14). In the present study, the results indicated that the growth of the transplanted colorectal tumor tissues from the mouse T2DM model was more rapid than that from the normal mice.…”

Section: Discussionmentioning

confidence: 61%

Changes in serum IGF-1 level and tumor VEGF expression in mice with colorectal cancer under hyperglycemic conditions

Cao

Jin²,

De-fang

et al. 2013

Molecular Medicine Reports

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Abstract. The present study aimed to observe the growth of transplanted tumors in mice with colorectal cancer (CRC) under hyperglycemic conditions and to detect the expression of vascular endothelial growth factor (VEGF) in these tumors. The study also aimed to observe the changes in serum insulin-like growth factor-1 (IGF-1) levels and to determine whether type 2 diabetes mellitus (T2DM) was a risk factor for the progression and development of CRC. A mouse model of a transplanted colorectal tumor with T2DM was established to observe the changes in volume and size of the transplanted tumor. Mice were sacrificed at the end of the 5th week to determine the serum IGF-1 level and VEGF expression in the tumor tissues. The tumor volume (1628.5±882 mm 3 ) in the CRC-DM group was larger than that in the CRC group (1950.2±726 mm 3 ; P<0.05). The serum IGF-1 level (105.33±32.32 ng/ml) was higher than that in the normal (69.83±25.57 ng/ml) and CRC groups (70.17±25.27 ng/ml; P<0.05). The VEGF expression in the tumor tissues of the CRC-DM group(70.0±11.5%) was higher than that in the CRC group (42.9±7.5%; P<0.05). T2DM may be one of the causes for the promotion of CRC growth and its mechanism may be correlated with the increased IGF-1 action observed in the blood that induces VEGF gene transcription, upregulates VEGF expression, causes tumor angiogenesis and thus leads to the occurrence and metastasis of tumors. IntroductionColorectal cancer (CRC) is the joint name for colon and rectal cancer, one of the most common malignant tumors. Numerous scholars have observed that the occurrence and development of CRC is closely correlated with diabetes mellitus (DM) (1-4). The studies observed that the mechanism of DM-induced CRC may include the following: i) hyperglycemia, ii) the role of hyperinsulinemia and insulin resistance, iii) the role of insulin-like growth factor-1 (IGF-1), iv) the role of metabolic syndrome-related inflammatory factors (including adipokines) (5) for cell proliferation, v) the role of the immune system and vi) the increase of plasma endothelin level in diabetics, as well as the abnormalities of various trace elements, including chrome, zinc, manganese, selenium, magnesium and ferrum. The incidence of colorectal tumors caused by the increased insulin secretion from certain hypoglycemic agents may also be involved. In the present study, in order to further demonstrate the correlation between these factors, a type 2 DM (T2DM) model was established based on a mouse model of a transplanted colorectal tumor. The changes in the mouse serum IGF-1 levels and the vascular endothelial growth factor (VEGF) expression were observed in the tumor in order to discuss whether type 2 diabetes was a significant risk factor for promoting the development and progression of CRC and to explain the possible mechanism behind this. The present study was conducted in the hope of providing a research basis for the prevention of CRC. Materials and methodsExperimental groups. ICR mice were purchased from the Shanghai SLAC Laboratory Anim...

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Frequent loss of imprinting of IGF2 and MEST in lung adenocarcinoma

Cited by 91 publications

References 46 publications

Altered expression of imprinted genes in Wilms tumors

Altered expression of imprinted genes in Wilms tumors

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Changes in serum IGF-1 level and tumor VEGF expression in mice with colorectal cancer under hyperglycemic conditions

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