Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer

Hu, Caroline; McCall, Shannon J.; Madden, John F.; Huang, Hong; Clough, Robert; Jirtle, Randy L.; Anscher, Mitchell S.

doi:10.1038/sj.pcan.4500842

Cited by 23 publications

(15 citation statements)

References 24 publications

(42 reference statements)

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“…However, some studies have shown that mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) gene can function as the tumor suppressor in cancer. M6P/IGF2R is found inactivated in prostate cancer and the mutation of this gene is an early event in the development of prostate cancer (14). M6P/IGF2R also functions as a growth suppressor, but the loss or mutation of this gene contributes to development and progression of some cancers (15,16) and is involved in HBV-associated hepatocarcinogenesis (17).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of IGF2R suppresses proliferation and induces apoptosis in hemangioma cells in vitro and in vivo

et al. 2014

International Journal of Oncology

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Abstract. Insulin-like growth factor-II (IGF-II)/IGF2R signaling plays a pivotal role in cell growth, migration and differentiation in many malignancies. An individual with high IGF-II expression levels has a high risk of developing cancer, but IGF2R is often considered to be a tumor suppressor. To date, little has been reported about the role of IGF-II/IGF2R signaling in hemangiomas (HAs). Thus, uncovering the mechanisms of IGF-II/IGF2R signaling is very important to understanding the development of HAs. In the present study, the expression of IGF-II and IGF2R was investigated in 27 cases of HAs of different phases by immunohistochemistry. Through lentivirus-mediated IGF2R siRNA (Lv-siIGF2R) in HA-derived endothelial cells (HDECs), we observed the effects of IGF2R knockdown on the biological behavior of HA cells. We found that the expression of IGF-II and IGF2R was significantly increased in proliferating phase HAs, but decreased in involuting phase HAs. Furthermore, knockdown of IGF2R in vitro significantly diminished the proliferative activity and induced apoptosis and cycle arrest with decreased expression of PCNA, Ki-67, Bcl-2, Cyclin D1 and E and increased the expression of Bax in the proliferative phase HAs (HDEC and CRL-2586 EOMA cells). In addition, the tumor volumes in a subcutaneous HDEC nude mouse model treated with Lv-siIGF2R were significantly smaller than those of the control group. Taken together, our findings indicate that the expression of IGF-II and IGF2R is increased in proliferating phase HAs, and knockdown of IGF2R suppresses proliferation and induces apoptosis in HA cells in vitro and in vivo, suggesting that IGF2R may represent a novel therapeutic target for the treatment of human HAs.

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Section: Introductionmentioning

confidence: 99%

Knockdown of IGF2R suppresses proliferation and induces apoptosis in hemangioma cells in vitro and in vivo

et al. 2014

International Journal of Oncology

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“…Several mutations inactivate and/or down-regulate IGF-2R [16], [40], [42], [45], resulting in increased levels of IGF-2, and increased signaling through IGF-1R [40]–[47]. We did not detect these specific mutations in our cell lines.…”

Section: Discussionmentioning

confidence: 62%

“…PCR reactants were purified with QIAquick spin columns (Qiagen) and sent to SeqWright, Inc. for sequencing. Other regions of the IGF-2R gene were also studied [16]. Polymorphisms were detected by comparing generated DNA sequences to reference sequences (NM_000876.2, NT_007422.13, and NW_001838991.2) using the web-based software blast.ncbi.nlm.nih.gov/Blast.cgi.…”

Section: Methodsmentioning

confidence: 99%

R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWS/FLI-1 siRNA in Ewing's Sarcoma: Convergence at the IGF/IGFR/Akt Axis

et al. 2011

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A subset of patients with Ewing's sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies. Mechanisms of sensitivity and resistance are unknown. We investigated whether an anti-IGF-1R antibody acts via a pathway that could also be suppressed by small interfering (si) RNA against the EWS/FLI-1 fusion protein, the hallmark of Ewing's sarcoma. The growth of two Ewing's sarcoma cell lines (TC-32 and TC-71) was inhibited by the fully human anti-IGF-1R antibody, R1507 (clonogenic and MTT assays). TC-32 and TC-71 cells express high levels of IGF-2, while RD-ES and A4573 Ewing's cell lines, which were less responsive to R1507 in our assays, express low or undetectable IGF-2, respectively. TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt. EWS/FLI-1 siRNA also decreased p-Akt, due to its ability to increase IGF-BP3 levels and subsequently decrease IGF-1 and IGF-2 levels, thus inhibiting signaling through p-IGF-1R. This inhibition correlated with growth suppression and apoptosis. The attenuation of Akt activation was confirmed in TC-71 and HEK-293 (human embryonic kidney) cells by transfecting them with IGF-1R siRNA. We conclude that antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF-1R signals that suppress a common point in this pathway, namely the phosphorylation of Akt.

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“…Disruption of IGF2R function has been implicated as a mechanism which increases cell proliferation, suggesting that this receptor may play the role of a growth inhibitor (31). LOH and mutations in the remaining allele at the IGF2R/M6P locus have been observed in hepatocellular carcinomas (32,33), breast tumors (34), ovarian cancer (35), prostate cancer (36) and squamous cell carcinoma of the lung (37). In addition, IGF2R/M6P has been observed in colorectal, gastric and endometrial tumors exhibiting MI (38,39).…”

Section: Discussionmentioning

confidence: 99%

A combined strategy of conventional cytogenetics, fluorescent in situ hybridization and microsatellite polymerase chain reaction to analyze the deletion of chromosome 6 in laryngeal squamous cell carcinoma

Kang

Li²,

Fu³

et al. 2007

Oncol Rep

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Abstract. Laryngeal squamous cell carcinoma (LSCC) is a common cancer of the upper respiratory tract. The cytogenetic and molecular events involved in the pathogenesis of LSCC are not well understood. In this study, a combined strategy of conventional cytogenetics, fluorescent in situ hybridization (FISH) and microsatellite polymerase chain reaction was performed to analyze the deletion of chromosome 6 in LSCC. Karyotype analysis indicated that the deletions of 6q were marker chromosomes potentially specific to LSCC. To further characterize the loss of 6q, metaphase cells derived from both solid tumors and the Hep-2 cell line were investigated using FISH, with results consistent with those of conventional cytogenetics. Moreover, tumor-adjacent normal tissue DNA pairs from 70 LSCC in China were analyzed for loss of heterozygosity (LOH) and microsatellite instability (MI) on chromosome 6q in the region 6q25 by polymerase chain reaction (PCR) and three microsatellite markers. Overall, the highest frequency of microsatellite alteration (68.2%) was located at D6S980, which revealed that the region around D6S980 in 6q25 might harbor some important genes related to the pathogenesis of LSCC in Chinese patients. The pattern of chromosomal changes detected using the combined strategy suggests that it will become the most suitable way to find novel cancer-related genes and discover the relationship between the aberration of genetics and their tumorigenic mechanism.

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Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer

Cited by 23 publications

References 24 publications

Knockdown of IGF2R suppresses proliferation and induces apoptosis in hemangioma cells in vitro and in vivo

Knockdown of IGF2R suppresses proliferation and induces apoptosis in hemangioma cells in vitro and in vivo

R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWS/FLI-1 siRNA in Ewing's Sarcoma: Convergence at the IGF/IGFR/Akt Axis

A combined strategy of conventional cytogenetics, fluorescent in situ hybridization and microsatellite polymerase chain reaction to analyze the deletion of chromosome 6 in laryngeal squamous cell carcinoma

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