Gene Summary

Gene:M6PR; mannose-6-phosphate receptor, cation dependent
Aliases: SMPR, MPR46, CD-MPR, MPR 46, MPR-46, CD-M6PR
Summary:This gene encodes a member of the P-type lectin family. P-type lectins play a critical role in lysosome function through the specific transport of mannose-6-phosphate-containing acid hydrolases from the Golgi complex to lysosomes. The encoded protein functions as a homodimer and requires divalent cations for ligand binding. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. A pseudogene of this gene is located on the long arm of chromosome X. [provided by RefSeq, May 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cation-dependent mannose-6-phosphate receptor
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Tumor Stem Cell Assay
  • IGF2R
  • IGF1R
  • Sulfites
  • Skin Cancer
  • Breast Cancer
  • Sodium Dodecyl Sulfate
  • Liver Cancer
  • Trophoblastic Neoplasms
  • Structure-Activity Relationship
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Hepatocellular Carcinoma
  • Species Specificity
  • Genetic Predisposition
  • Tumor Suppressor Gene
  • Statistics as Topic
  • Loss of Heterozygosity
  • Frameshift Mutation
  • bcl-2-Associated X Protein
  • Proto-Oncogene Proteins
  • Cancer Gene Expression Regulation
  • Microsatellite Repeats
  • Messenger RNA
  • TNF
  • Transcription
  • DNA-Binding Proteins
  • Mutation
  • Receptor, Transforming Growth Factor-beta Type II
  • Base Sequence
  • IGF2
  • Polymerase Chain Reaction
  • Tamoxifen
  • Trans-Activators
  • Receptors, Colony-Stimulating Factor
  • Cancer DNA
  • Chromosome 12
  • BCL2 protein
  • Transforming Growth Factor beta Receptors
  • Survival Rate
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: M6PR (cancer-related)

Lautem A, Simon F, Hoppe-Lotichius M, et al.
Expression and prognostic significance of insulin‑like growth factor-2 receptor in human hepatocellular carcinoma and the influence of transarterial chemoembolization.
Oncol Rep. 2019; 41(4):2299-2310 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common human malignancies, the incidence of which is growing worldwide. The prognosis of HCC is very poor and it is often accompanied by a high rate of recurrence. Conventional chemotherapeutic approaches are largely inefficient. In order to develop novel effective methods for the early detection and prognosis of HCC, novel markers and therapeutic targets are urgently required. The present study focused on the effects of the expression of the tumor suppressor gene insulin‑like growth factor‑2 receptor (IGF2R) on patient survival and tumor recurrence in patients with HCC; this study paid specific attention to the influence of transarterial chemoembolization (TACE) prior to surgery. The mRNA expression levels of IGF2R were measured in primary human HCC and corresponding non‑neoplastic tumor‑surrounding tissue (TST) by reverse transcription‑polymerase chain reaction (RT‑PCR) (n=92). Subsequently, the associations between IGF2R expression and clinicopathological parameters, outcomes of HCC and TACE pretreatment prior to surgery were determined. Furthermore, the effects of the IGF2R gene polymorphisms rs629849 and rs642588 on susceptibility and on clinicopathological features of HCC were investigated. RT‑PCR demonstrated that the mRNA expression levels of IGF2R were downregulated in HCC compared with in TST samples (P=0.004), which was associated with a worse recurrence‑free survival of patients with HCC (P=0.002) and a lower occurrence of cirrhosis (P=0.05). TACE‑pretreated patients with HCC (n=26) exhibited significantly higher IGF2R mRNA expression in tumor tissues (P=0.019). In addition, significantly more patients with HCC in the TACE‑pretreated group exhibited upregulated IGF2R mRNA expression compared with in the non‑treated patients (P=0.032). The IGF2R SNPs rs629849 and rs642588 were not significantly associated with HCC risk, whereas a homozygous IGF2R rs629849 GG genotype was associated with a significantly elevated risk of non‑viral liver cirrhosis (P=0.05). In conclusion, these data suggested an important role for IGF2R expression in HCC, particularly with regards to TACE treatment prior to surgery.

Iida Y, Salomon MP, Hata K, et al.
Predominance of triple wild-type and IGF2R mutations in mucosal melanomas.
BMC Cancer. 2018; 18(1):1054 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment.
METHODS: Forty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry.
RESULTS: Mutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002).
CONCLUSIONS: These findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.

Chen H, Wang J, Zhuang Y, Wu H
Identification of the potential molecular mechanism and driving mutations in the pathogenesis of familial intestinal gastric cancer by whole exome sequencing.
Oncol Rep. 2018; 40(4):2316-2324 [PubMed] Related Publications
The genetic alterations in familial intestinal gastric cancer (FIGC) have not been clearly understood. Aiming to explore the molecular basis and the driving mutations underlying the pathogenesis of FIGC, we performed exome sequencing of the blood samples of the members of an extended family with FIGC. The differences in mutation patterns between family members with gastric cancer and controls were analysed and the overlapped variants were screened by comparing previously published data for blood and tumours from gastric cancer patients. The overlapped genes harbouring insertions‑deletions (INDELs) and single‑nucleotide variants (SNVs) were subjected to function, pathway and network analysis. The INDELs were enriched in DNA packaging and in the neurological system process related to the biological process (BP), while SNVs were closely related to cell‑function‑related BPs. ESR was the significant node with marked centrality in the SNV network. ERK 1/2 was the hub node in the INDEL network, interacting with EZK and IGF2R. Sequencing analysis revealed ESR1 homozygous mutations in exon 1 (216G > C) and exon 10 (2234C > T) and EZR1 heterozygous deletion of 68‑69 GT nucleotides in exon 13 of the family members. The IGF2R gene only demonstrated a mutation in exon 48 of the propositus. All hub proteins had direct or indirect interactions in the protein‑protein interaction network.

Bannoud N, Carvelli FL, Troncoso M, et al.
Cation-dependent mannose-6-phosphate receptor expression and distribution are influenced by estradiol in MCF-7 breast cancer cells.
PLoS One. 2018; 13(8):e0201844 [PubMed] Free Access to Full Article Related Publications
Cancer cells secrete procathepsin D, and its secretion is enhanced by estradiol. Although alterations in the pro-enzyme intracellular transport have been reported, the mechanism by which it is secreted remains poorly understood. In this work, we have studied the influence of estradiol on the expression and distribution of the cation-dependent mannose-6-phosphate receptor (CD-MPR), which would be a key molecule to ensure the proper localization of the enzyme to lysosomes in breast cancer cells. Immunoblotting studies demonstrated that the expression of CD-MPR is higher in MCF-7 cells, as compared to other breast cancer and non-tumorigenic cells. This expression correlated with high levels of cathepsin D (CatD) in these cells. By immunofluorescence, this receptor mostly co-localized with a Golgi marker in all cell types, exhibiting an additional peripheral labelling in MCF-7 cells. In addition, CD-MPR showed great differences regarding to cation-independent mannose-6-phosphate receptor. On the other hand, the treatment with estradiol induced an increase in CD-MPR and CatD expression and a re-distribution of both proteins towards the cell periphery. These effects were blocked by the anti-estrogen tamoxifen. Moreover, a re-distribution of CD-MPR to plasma membrane-enriched fractions, analyzed by gradient centrifugation, was observed after estradiol treatment. We conclude that, in hormone-responsive breast cancer cells, CD-MPR and CatD are distributed together, and that their expression and distribution are influenced by estradiol. These findings strongly support the involvement of the CD-MPR in the pro-enzyme transport in MCF-7 cells, suggesting the participation of this receptor in the procathepsin D secretion previously reported in breast cancer cells.

Pickard A, Durzynska J, McCance DJ, Barton ER
The IGF axis in HPV associated cancers.
Mutat Res Rev Mutat Res. 2017 Apr - Jun; 772:67-77 [PubMed] Related Publications
Human papillomaviruses (HPV) infect and replicate in stratified epithelium at cutaneous and mucosal surfaces. The proliferation and maintenance of keratinocytes, the cells which make up this epithelium, are controlled by a number of growth factor receptors such as the keratinocyte growth factor receptor (KGFR, also called fibroblast growth factor receptor 2b (FGFR2b)), the epithelial growth factor receptor (EGFR) and the insulin-like growth factor receptors 1 and 2 (IGF1R and IGF2R). In this review, we will delineate the mutation, gene transcription, translation and processing of the IGF axis within HPV associated cancers. The IGFs are key for developmental and postnatal growth of almost all tissues; we explore whether this crucial axis has been hijacked by HPV.

Li T, Wang J, Liu P, et al.
Insulin-like growth factor 2 axis supports the serum-independent growth of malignant rhabdoid tumor and is activated by microenvironment stress.
Oncotarget. 2017; 8(29):47269-47283 [PubMed] Free Access to Full Article Related Publications
Malignant rhabdoid tumors (MRTs) are rare, lethal, pediatric tumors predominantly found in the kidney, brain and soft tissues. MRTs are driven by loss of tumor suppressor SNF5/INI1/SMARCB1/BAF47. The prognosis of MRT is poor using currently available treatments, so new treatment targets need to be identified to expand treatment options for patients experiencing chemotherapy resistance. The growth hormone insulin-like growth factor 2 (IGF2) signaling pathway is a promising target to overcome drug resistance in many cancers. Here, we evaluated the role of IGF2 axis in MRT cell proliferation. We showed that microenvironment stress, including starvation treatment and chemotherapy exposure, lead to elevated expression of IGF2 in the SNF5-deficient MRT cell line. The autocrine IGF2, in turn, activated insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), followed by PI3K/AKT pathway and RAS/ERK pathway to promote cancer cell proliferation and survival. We further demonstrated that impairment of IGF2 signaling by IGF2 neutralizing antibody, IGF1R inhibitor NVP-AEW541 or AKT inhibitor MK-2206 2HCl treatment prevented MRT cell growth in vitro. Taken together, our characterization of this axis defines a novel mechanism for MRT cell growth in the microenvironment of stress. Our results also demonstrated the necessity to test the treatment effect targeting this axis in future research.

Mohlin S, Hamidian A, von Stedingk K, et al.
PI3K-mTORC2 but not PI3K-mTORC1 regulates transcription of HIF2A/EPAS1 and vascularization in neuroblastoma.
Cancer Res. 2015; 75(21):4617-28 [PubMed] Related Publications
Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors. Differential expression of the HIF subunits HIF1α and HIF2α occurs in many human tumor types, suggesting selective implications to biologic context. For example, high expression of HIF2α that occurs in neuroblastoma is associated with stem cell-like features, disseminated disease, and poor clinical outcomes, suggesting pivotal significance for HIF2 control in neuroblastoma biology. In this study, we provide novel insights into how HIF2α expression is transcriptionally controlled by hypoxia and how this control is abrogated by inhibition of insulin-like growth factor-1R/INSR-driven phosphoinositide 3-kinase (PI3K) signaling. Reducing PI3K activity was sufficient to decrease HIF2α mRNA and protein expression in a manner with smaller and less vascularized tumors in vivo. PI3K-regulated HIF2A mRNA expression was independent of Akt or mTORC1 signaling but relied upon mTORC2 signaling. HIF2A mRNA was induced by hypoxia in neuroblastoma cells isolated from metastatic patient-derived tumor xenografts, where HIF2A levels could be reduced by treatment with PI3K and mTORC2 inhibitors. Our results suggest that targeting PI3K and mTORC2 in aggressive neuroblastomas with an immature phenotype may improve therapeutic efficacy.

Bin BH, Bhin J, Yang SH, et al.
Hyperosmotic stress reduces melanin production by altering melanosome formation.
PLoS One. 2014; 9(8):e105965 [PubMed] Free Access to Full Article Related Publications
Many tissues of the human body encounter hyperosmotic stress. The effect of extracellular osmotic changes on melanin production has not yet been elucidated. In this study, we determined that hyperosmotic stress induced by organic osmolytes results in reduced melanin production in human melanoma MNT-1 cells. Under hyperosmotic stress, few pigmented mature melanosomes were detected, but there was an increase in swollen vacuoles. These vacuoles were stained with an anti-M6PR antibody that recognizes late endosomal components and with anti-TA99 and anti-HMB45 antibodies, implying that melanosome formation was affected by hyperosmotic stress. Electron microscopic analysis revealed that the M6PR-positive swollen vacuoles were multi-layered and contained melanized granules, and they produced melanin when L-DOPA was applied, indicating that these vacuoles were still capable of producing melanin, but the inner conditions were not compatible with melanin production. The vacuolation phenomenon induced by hyperosmotic conditions disappeared with treatment with the PI3K activator 740 Y-P, indicating that the PI3K pathway is affected by hyperosmotic conditions and is responsible for the proper formation and maturation of melanosomes. The microarray analysis showed alterations of the vesicle organization and transport under hyperosmotic stress. Our findings suggest that melanogenesis could be regulated by physiological conditions, such as osmotic pressure.

Ou JM, Lian WS, Qiu MK, et al.
Knockdown of IGF2R suppresses proliferation and induces apoptosis in hemangioma cells in vitro and in vivo.
Int J Oncol. 2014; 45(3):1241-9 [PubMed] Related Publications
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.

Rashad NM, El-Shal AS, Abd Elbary EH, et al.
Impact of insulin-like growth factor 2, insulin-like growth factor receptor 2, insulin receptor substrate 2 genes polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma.
Cytokine. 2014; 68(1):50-8 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Insulin-like growth factor-2 (IGF-2) is an important autocrine and paracrine growth factor which may induce cell proliferation and inhibit cell apoptosis leading to the transformation of normal cells into malignant cells. This study aimed to evaluate the possible roles of IGF-2, insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor substrate (IRS)-2 genes polymorphisms in susceptibility and clinicopathological features of HCC in Egyptian population.
MATERIALS AND METHODS: Four hundred and twenty-six HCC patients and 334 controls were enrolled in the study. Polymorphisms of IGF-2+3580, IGF-2+3123, IGF-2R 1619, and IRS-2 1057 gene were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum IGF-2 were determined using ELISA.
RESULTS: Serum IGF-2 levels were significantly lower in HCC patients than in healthy controls. IGF-2+3580 AA genotype, IGF-2+3123 GG genotype or G allele, IRS-2 1057 DD genotype and D allele were significantly associated with HCC risk. The combination of IGF-2+3580 AA homozygosity and IGF-2R 1619 GG homozygosity presented a significant protective effect against HCC (OR=0.16,95% CI=0. 08-0.34, P=0. 005). Serum IGF-2 concentrations were significantly increased in HCC patients with the IGF-2+3580 AA genotype. We also observed that increased alpha-fetoprotein (AFP), Child-Pugh grade, tumor size, and number of malignant lesions were accompanied by a significant increase of serum IGF-2 mean values of in HCC patients.
CONCLUSION: IGF-2, IGF-2R, and IRS-2 genes polymorphisms and their combinations are associated with risk of HCC.

Kubisch R, Fröhlich T, Arnold GJ, et al.
V-ATPase inhibition by archazolid leads to lysosomal dysfunction resulting in impaired cathepsin B activation in vivo.
Int J Cancer. 2014; 134(10):2478-88 [PubMed] Related Publications
The myxobacterial agent archazolid inhibits the vacuolar proton pump V-ATPase. V-ATPases are ubiquitously expressed ATP-dependent proton pumps, which are known to regulate the pH in endomembrane systems and thus play a crucial role in endo- and exocytotic processes of the cell. As cancer cells depend on a highly active secretion of proteolytic proteins in order to invade tissue and form metastases, inhibition of V-ATPase is proposed to affect the secretion profile of cancer cells and thus potentially abrogate their metastatic properties. Archazolid is a novel V-ATPase inhibitor. Here, we show that the secretion pattern of archazolid treated cancer cells includes various prometastatic lysosomal proteins like cathepsin A, B, C, D and Z. In particular, archazolid induced the secretion of the proforms of cathepsin B and D. Archazolid treatment abrogates the cathepsin B maturation process leading to reduced intracellular mature cathepsin B protein abundance and finally decreased cathepsin B activity, by inhibiting mannose-6-phoshate receptor-dependent trafficking. Importantly, in vivo reduced cathepsin B protein as well as a decreased proteolytic cathepsin B activity was detected in tumor tissue of archazolid-treated mice. Our results show that inhibition of V-ATPase by archazolid reduces the activity of prometastatic proteases like cathepsin B in vitro and in vivo.

Caixeiro NJ, Martin JL, Scott CD
Silencing the mannose 6-phosphate/IGF-II receptor differentially affects tumorigenic properties of normal breast epithelial cells.
Int J Cancer. 2013; 133(11):2542-50 [PubMed] Related Publications
Although loss of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) in breast cancer is believed to play a role in tumorigenesis, it has not been demonstrated that M6P/IGF-IIR loss is sufficient to confer a malignant phenotype in an untransformed cell. We investigated the impact of M6P/IGF-IIR silencing using phenotypically normal (MCF-10A) and oncogenically transformed (MCF-10T, the c-Ha-ras transformed derivative of MCF-10A) human breast epithelial cell lines as model systems. In both cell lines, silencing of M6P/IGF-IIR increased cell proliferation and motility, with the effects being more pronounced in MCF-10A cells. Although anchorage-independent growth was increased by M6P/IGF-IIR silencing in MCF-10T cells, MCF-10A cells did not acquire the ability to grow in soft agar. Conversely, reduced M6P/IGF-IIR expression increased the invasive potential of MCF-10A cells, but did not enhance the already high rate of invasion of MCF-10T cells. M6P/IGF-IIR silencing had no effect on basal or IGF-II-stimulated IGF-I receptor (IGF-IR) or AKT phosphorylation in either cell line, but both were abrogated by IGF-IR kinase inhibition, which also reduced the stimulatory effect of M6P/IGF-IIR silencing on proliferation under basal and IGF-II-stimulated conditions in both cell lines. However, cell motility was neither stimulated by IGF-II nor reduced by IGF-IR inhibition, suggesting that potentiation of specific tumorigenic features in response to M6P/IGF-IIR silencing involves IGF-II- dependent and -independent mechanisms. Collectively, these data suggest that M6P/IGF-IIR silencing alone is insufficient to confer a tumorigenic phenotype, but can enhance tumorigenicity in an already transformed cell.

Mountzios G, Kostopoulos I, Kotoula V, et al.
Insulin-like growth factor 1 receptor (IGF1R) expression and survival in operable squamous-cell laryngeal cancer.
PLoS One. 2013; 8(1):e54048 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Prognosis of patients with operable laryngeal cancer is highly variable and therefore potent prognostic biomarkers are warranted. The insulin-like growth factor receptor (IGFR) signaling pathway plays a critical role in laryngeal carcinogenesis and progression.
PATIENTS AND METHODS: We identified all patients with localized TNM stage I-III laryngeal cancer managed with potentially curative surgery between 1985 and 2008. Immunohistochemical (IHC) expression of IGF1R-alpha, IGF1R-beta and IGF2R was evaluated using the immunoreactive score (IRS) and mRNA levels of important effectors of the IGFR pathway were assessed, including IGF1R, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) and members of the MAP-kinase (MAP2K1, MAPK9) and phosphatidyl-inositol-3 kinase (PIK3CA, PIK3R1) families. Cox-regression models were applied to assess the predictive value of biomarkers on disease-free survival (DFS) and overall survival (OS).
RESULTS: Among 289 eligible patients, 95.2% were current or ex smokers, 75.4% were alcohol abusers, 15.6% had node-positive disease and 32.2% had received post-operative irradiation. After a median follow-up of 74.5 months, median DFS was 94.5 months and median OS was 106.3 months. Using the median IRS as the pre-defined cut-off, patients whose tumors had increased IGF1R-alpha cytoplasm or membrane expression experienced marginally shorter DFS and significantly shorter OS compared to those whose tumors had low IGF1R-alpha expression (91.1 vs 106.2 months, p = 0.0538 and 100.3 vs 118.6 months, p = 0.0157, respectively). Increased mRNA levels of MAPK9 were associated with prolonged DFS (p = 0.0655) and OS (p = 0.0344). In multivariate analysis, IGF1R-alpha overexpression was associated with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors for poor OS included node-positive disease (HR = 2.569, p<0.0001), subglottic/transglottic localization (HR = 1.756, p = 0.0438) and IGF1R-alpha protein overexpression (HR = 1.475, p = 0.0504).
CONCLUSION: IGF1R-alpha protein overexpression may serve as an independent predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation of the IGF1R-alpha prognostic utility is warranted.

Morrione A, Neill T, Iozzo RV
Dichotomy of decorin activity on the insulin-like growth factor-I system.
FEBS J. 2013; 280(10):2138-49 [PubMed] Free Access to Full Article Related Publications
The stromal-specific proteoglycan decorin has emerged in recent years as a critical regulator of tumor initiation and progression. Decorin regulates the biology of various types of cancer by modulating the activity of several receptor tyrosine kinases coordinating growth, survival, migration, and angiogenesis. Decorin binds to surface receptors for epidermal growth factor and hepatocyte growth factor with high affinity, and negatively regulates their activity and signaling via robust internalization and eventual degradation. The insulin-like growth factor (IGF)-I system plays a critical role in the regulation of cell growth both in vivo and in vitro. The IGF-I receptor (IGF-IR) is also essential for cellular transformation, owing to its ability to enhance cell proliferation and protect cancer cells from apoptosis. Recent data have pointed to a role of decorin in regulating the IGF-I system in both nontransformed and transformed cells. Significantly, there is a surprising dichotomy in the mechanism of decorin action on IGF-IR signaling, which differs considerably between physiological and pathological cellular models. In this review, we summarize the current knowledge on decorin regulation of the IGF-I system in normal and transformed cells, and discuss possible decorin-based therapeutic approaches to target IGF-IR-driven tumors.

Bergman D, Halje M, Nordin M, Engström W
Insulin-like growth factor 2 in development and disease: a mini-review.
Gerontology. 2013; 59(3):240-9 [PubMed] Related Publications
BACKGROUND: Insulin-like growth factor 2 (IGF2) is a protein hormone known to regulate cell proliferation, growth, migration, differentiation and survival. The gene is parentally imprinted in the sense that transcripts are almost exclusively derived from the paternal allele. Loss of imprinting of the IGF2 gene is a recurrent observation in growth disorders that combine overgrowth with a variety of malignant tumours. Moreover, IGF2 has been proposed to play a role in the development of a variety of seemingly unrelated cancers that play an important role in geriatric medicine, e.g., breast cancer, colon cancer and lung cancer. Finally, IGF2 has been implicated in cardiovascular disease, since, for example, IGF2 has been shown to influence the size of atherosclerotic lesions.
OBJECTIVE: To summarize current knowledge about IGF2, its interactions with binding proteins and receptors and connections with key diseases.
METHODS: The contents of this paper were based on reviews of existing literature within the field.
RESULTS: There is a substantial amount of research linking IGF2 to growth disorders, cancer and to a much lesser degree cardiovascular disease. Some of the studies on IGF2 and tumour growth have yielded conflicting results, for instance regarding its effect on apoptosis.
CONCLUSION: Today, our knowledge on how IGF2 is composed and interacts with receptors has come a long way. However, there is comparatively little information on how IGF2 affects tumour growth and cardiovascular diseases such as atherosclerosis. Thus, further research will be needed to elucidate the impact of IGF2 on key diseases.

Kreiling JL, Montgomery MA, Wheeler JR, et al.
Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer.
FEBS J. 2012; 279(15):2695-713 [PubMed] Free Access to Full Article Related Publications
Oligomerization of the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is important for optimal ligand binding and internalization. M6P/IGF2R is a tumor suppressor gene that exhibits loss of heterozygosity and is mutated in several cancers. We tested the potential dominant-negative effects of two cancer-associated mutations that truncate M6P/IGF2R in ectodomain repeats 9 and 14. Our hypothesis was that co-expression of the truncated receptors with the wild-type/endogenous full-length M6P/IGF2R would interfere with M6P/IGF2R function by heterodimer interference. Immunoprecipitation confirmed formation of heterodimeric complexes between full-length M6P/IGF2Rs and the truncated receptors, termed Rep9F and Rep14F. Remarkably, increasing expression of either Rep9F or Rep14F provoked decreased levels of full-length M6P/IGF2Rs in both cell lysates and plasma membranes, indicating a dominant-negative effect on receptor availability. Loss of full-length M6P/IGF2R was not due to increased proteasomal or lysosomal degradation, but instead arose from increased proteolytic cleavage of cell-surface M6P/IGF2Rs, resulting in ectodomain release, by a mechanism that was inhibited by metal ion chelators. These data suggest that M6P/IGF2R truncation mutants may contribute to the cancer phenotype by decreasing the availability of full-length M6P/IGF2Rs to perform tumor-suppressive functions such as binding/internalization of receptor ligands such as insulin-like growth factor II.

Takahashi Y, Mimori K, Yamamoto K, et al.
Genomic copy number of a carcinogenic single nucleotide polymorphism at 8q24 in non-risk allele colorectal cancer associated with insulin growth factor 2 receptor expression.
J Gastroenterol Hepatol. 2012; 27 Suppl 3:95-9 [PubMed] Related Publications
BACKGROUND AND AIM: The incidence of both diabetes mellitus and hyperlipidemia is increasing and they are risk factors for colorectal cancer (CRC). On the other hand, the carcinogenic significance of the single nucleotide polymorphism (SNP), rs6983267 at 8q24, in CRC has been reported. The association between the SNP genotype and genes associated with diabetes or hyperlipidemia was investigated in cases of CRC.
METHODS: In 107 cases of CRC diagnosed in eight institutes from 2003 to 2008, array-CGH and cDNA microarray was performed and the data analyzed from two groups subdivided according to SNP genotype.
RESULTS: In the array-CGH data, we selected 38 genes related to diabetes or fat metabolism, and of these 10 had a correlation coefficient between the genome copy number at 8q24 locus and that of each gene. Of the 10 genes, insulin growth factor 2 receptor (IGF2R) was the only one with an expression level significantly associated with the 8q24 genotype. IGF2R expression was significantly lower in non-risk allele than in risk allele cases (P = 0.012). There was neither a diabetes- nor a fat metabolism-related gene that was significantly associated with CRC cases with the risk allele at 8q24.
CONCLUSIONS: SNP at 8q24 makes diabetes a risk factor of CRC via IGF2R, especially in genetically non-risk allele cases. We speculate that the risk allele of 8q24 might be risky enough that diabetes is not necessary to worsen the risk for CRC.

Hartmann EM, Beà S, Navarro A, et al.
Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression.
Mod Pathol. 2012; 25(9):1227-35 [PubMed] Related Publications
Mantle cell lymphoma is an aggressive, non-curable B-cell lymphoma, characterized by the translocation t(11;14)(q13;q32) involving CCND1 and a high number of additional genetic alterations. Chromosomal gains of 7p are frequent in mantle cell lymphoma, with insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3 aka IMP3) being the most upregulated gene in this region. IGF2BP3 is a member of the IGF II mRNA-BP family, and increased IGF2BP3 expression is associated with an aggressive behavior in many malignant tumors. We here analyze selected genes related to IGF signaling in gene expression and genomic array data of 8 mantle cell lymphoma cell lines and 12 primary mantle cell lymphomas and study IGF2BP3 protein expression in 172 well-characterized primary mantle cell lymphomas by immunohistochemistry. The majority of mantle cell lymphoma cell lines and primary cases showed elevated IGF2BP3 mRNA expression and a subset also expressed the IGF1 and IGF2 receptors. On the protein level, 66 of 172 primary mantle cell lymphomas showed IGF2BP3 expression in >50% of tumor cells, and strong IGF2BP3 protein expression was highly associated with increased proliferation as measured by the Ki-67 index, but not with overall survival of mantle cell lymphoma patients. Only a subset of mantle cell lymphomas with marked IGF2BP3 expression had an underlying chromosomal gain in 7p, suggesting that additional mechanisms are involved in the upregulation of IGF2BP3 in mantle cell lymphoma. In seven paired mantle cell lymphoma samples, IGF2BP3 protein expression remained constant between primary diagnosis and relapse. Increased IGF2BP3 expression and, potentially, enhanced IGF signaling may contribute proproliferative stimuli in the evolution of mantle cell lymphoma tumor cells.

Puxbaum V, Nimmerfall E, Bäuerl C, et al.
M6P/IGF2R modulates the invasiveness of liver cells via its capacity to bind mannose 6-phosphate residues.
J Hepatol. 2012; 57(2):337-43 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R), a multifunctional protein, plays a central role in intracellular targeting of lysosomal enzymes and control of insulin-like growth factor II (IGF-II) bioactivity. Importantly, the gene encoding this receptor is frequently inactivated in a wide range of malignant tumors including hepatocellular carcinomas. Thus, M6P/IGF2R is considered a putative liver tumor suppressor. The aim of this study was to establish the impact of the receptor on the invasive properties of liver cells.
METHODS: Reconstitution experiments were performed by expression of wild type and mutant M6P/IGF2R in receptor-deficient FRL14 fetal rat liver cells. RNA interference was used to induce M6P/IGF2R downregulation in receptor-positive MIM-1-4 mouse hepatocytes.
RESULTS: We show that the M6P/IGF2R status exerts a strong impact on the invasiveness of tumorigenic rodent liver cells. M6P/IGF2R-deficient fetal rat liver cells hypersecrete lysosomal cathepsins and penetrate extracellular matrix barriers in a cathepsin-dependent manner. Forced expression of M6P/IGF2R restores intracellular transport of cathepsins to lysosomes and concomitantly reduces the tumorigenicity and invasive potential of these cells. Conversely, M6P/IGF2R knock-down in receptor-positive mouse hepatocytes causes increased cathepsin secretion as well as enhanced cell motility and invasiveness. We also demonstrate that functional M6P-binding sites are important for the anti-invasive properties of M6P/IGF2R, whereas the capacity to bind IGF-II is dispensable for the anti-invasive activity of the receptor in liver cells.
CONCLUSIONS: M6P/IGF2R restricts liver cell invasion by preventing the pericellular action of M6P-modified proteins.

Kuhlmann JD, Schwarzenbach H, Otterbach F, et al.
Loss of heterozygosity proximal to the M6P/IGF2R locus is predictive for the presence of disseminated tumor cells in the bone marrow of ovarian cancer patients before and after chemotherapy.
Genes Chromosomes Cancer. 2011; 50(8):598-605 [PubMed] Related Publications
Disseminated tumor cells (DTC) in the bone marrow (BM) are present in about 35% of ovarian cancers before surgery and after chemotherapy and are associated with worse prognosis. A molecular biomarker in the primary tumor predicting tumor cell spread would be highly desirable. The purpose of the study was to investigate loss of heterozygosity (LOH) in primary ovarian tumors at four ovarian cancer-relevant chromosomal loci involved in apoptosis, platinum sensitivity, or DNA-repair, to assess the prognostic value of LOH and to correlate LOH with DTC occurrence before surgery and after chemotherapy. Primary tumor DNA of 88 patients was analyzed for LOH at four polymorphic microsatellite markers using PCR-based fluorescence microsatellite analysis. BM aspirates were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. LOH at the entire marker set correlated with tumor grading (P = 0.0001) and histology (P = 0.004). LOH at marker D10S1765 correlated with FIGO stage (P = 0.046) and grading (P = 0.05), whereas LOH at D17S855 significantly associated with grading (P = 0.023) and histology (P = 0.012), respectively. DTC were detected in 49% of patients before surgery and in 50% of patients after chemotherapy. Interestingly, LOH proximal to D6S1581 significantly correlated with DTC presence before surgery (P = 0.05) and after chemotherapy (P = 0.022). Conclusively, our data suggest that allelic loss at D6S1581 (proximal to M6P/IGF2R locus) serves as a molecular biomarker for the presence of DTC in the BM before and after chemotherapy.

Tworkoski K, Singhal G, Szpakowski S, et al.
Phosphoproteomic screen identifies potential therapeutic targets in melanoma.
Mol Cancer Res. 2011; 9(6):801-12 [PubMed] Free Access to Full Article Related Publications
Therapies directed against receptor tyrosine kinases are effective in many cancer subtypes, including lung and breast cancer. We used a phosphoproteomic platform to identify active receptor tyrosine kinases that might represent therapeutic targets in a panel of 25 melanoma cell strains. We detected activated receptors including TYRO3, AXL, MERTK, EPHB2, MET, IGF1R, EGFR, KIT, HER3, and HER4. Statistical analysis of receptor tyrosine kinase activation as well as ligand and receptor expression indicates that some receptors, such as FGFR3, may be activated via autocrine circuits. Short hairpin RNA knockdown targeting three of the active kinases identified in the screen, AXL, HER3, and IGF1R, inhibited the proliferation of melanoma cells and knockdown of active AXL also reduced melanoma cell migration. The changes in cellular phenotype observed on AXL knockdown seem to be modulated via the STAT3 signaling pathway, whereas the IGF1R-dependent alterations seem to be regulated by the AKT signaling pathway. Ultimately, this study identifies several novel targets for therapeutic intervention in melanoma.

Malaguarnera R, Frasca F, Garozzo A, et al.
Insulin receptor isoforms and insulin-like growth factor receptor in human follicular cell precursors from papillary thyroid cancer and normal thyroid.
J Clin Endocrinol Metab. 2011; 96(3):766-74 [PubMed] Related Publications
CONTEXT: Factors involved in the biology of normal and cancer stem/precursor cells from the thyroid are unknown. Thyroid cancer cells are responsive to insulin and IGF-I and IGF-II and often overexpress the insulin receptor (IR) and the IGF-I receptor (IGF-IR).
OBJECTIVE: We investigated the role of IR isoforms (IR-A and IR-B), IGF-IR, and their ligands in thyroid follicular cell precursors both normal and malignant.
DESIGN: We established cultures of follicular cell precursors as thyrospheres from three papillary thyroid cancers and the corresponding nonaffected tissues. The expression of IR, IGF-IR, and their ligands was evaluated by quantitative RT-PCR and, in one case, also by Western blot. The effects of insulin and IGFs on thyrosphere growth and self-renewal were evaluated.
RESULTS: Thyrospheres were characterized by the expression of stem cell markers and low/absent thyroid specific markers. Thyrospheres from normal tissue, but not from cancer tissue, could be induced to differentiate. Both IR isoforms, IGF-IR, IGF-I and IGF-II, were expressed at high levels in thyrospheres and markedly decreased in differentiating cells. IR-A was the predominant isoform in thyrospheres, especially from cancer, while IR-B was predominant in differentiating cells. Cancer thyrosphere growth was stimulated by insulin and IGFs.
CONCLUSIONS: Our data suggest that IR isoforms and IGF-IR play a role in the biology of follicular thyroid precursors. Cell differentiation is associated with marked changes in the expression of these receptors and cognate ligands. These data may provide insight for future differentiation therapies in thyroid cancer.

Yashiro M, Hirakawa K, Boland CR
Mutations in TGFbeta-RII and BAX mediate tumor progression in the later stages of colorectal cancer with microsatellite instability.
BMC Cancer. 2010; 10:303 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Microsatellite instability (MSI) occurs in 15% of colorectal cancers (CRC). The genetic targets for mutation in the MSI phenotype include somatic mutations in the transforming growth factor beta receptor typeII (TGFbetaRII), BAX, hMSH3 and hMSH6. It is not clear how mutations of these genes mediate tumor progression in the MSI pathway, and the temporal sequence of these mutations remains uncertain. In this study, early stage CRCs were examined for frameshift mutations in these target genes, and compared with late stage tumors and CRC cell lines.
METHODS: We investigated 6 CRC cell lines and 71 sporadic CRCs, including 61 early stage cancers and 10 late stage cancers. Mutations of repetitive mononucleotide tracts in the coding regions of TGFbetaRII, BAX, hMSH3, hMSH6, IGFIIR and Fas antigen were identified by direct sequencing.
RESULTS: Thirteen (18.3%) of 71 CRC, including 9/61 (14.7%) early stage cancers and 4/10 (40%) late stage cancers, were identified as MSI and analyzed for frameshift mutations. No mutation in the target genes was observed in any of the 9 early stage MSI CRCs. In contrast, frameshift mutations of TGFbetaRII, BAX, hMSH3 and hMSH6 were present in 3/4 late stage MSI tumors. There is a statistical association (p = 0.014) between mutation in any one gene and tumor stage.
CONCLUSIONS: TGFbetaRII, BAX, hMSH3 and hMSH6 mutations are relatively late events in the genesis of MSI CRCs. The frameshift mutations in these target genes might mediate progression from early to late stage cancer, rather than mediating the adenoma to carcinoma transition.

Bidosee M, Karry R, Weiss-Messer E, Barkey RJ
Growth hormone affects gene expression and proliferation in human prostate cancer cells.
Int J Androl. 2011; 34(2):124-37 [PubMed] Related Publications
We previously showed that growth hormone (GH) receptors (GHR) are expressed in the most commonly studied human prostate cancer (PCa) cell lines and that GHR isoforms undergo differential, cell-type-specific hormonal regulation. We now report that human GH (hGH) can stimulate/modulate insulin-like growth factor (IGF) and β-oestradiol (E(2) ) receptor (ER(β) ) gene expressions in these cells and interact with IGF-I and E(2) to stimulate androgen-dependent LNCaP cell proliferation. We observed a cell type-dependent, differential regulation of IGF axis gene expression by GH: IGF-I was stimulated in the androgen-dependent LNCaP cells; IGF-II was stimulated in androgen-insensitive (AI) PC3 cells; the IGF-I cognate receptor, IGF-IR, was stimulated in LNCaP cells, but inhibited in PC3 cells; IGF-IIR was stimulated in both LNCaP and PC3 cells. GH also stimulated ER(β) gene expression in LNCaP and PC3 cells, but had little or no effect on any of those genes in AI DU145 cells. The potent androgen analogue, mibolerone, also stimulated IGF-I, IGF-IR and ER(β) , but reduced IGF-IIR mRNAs in LNCaP cells. Furthermore, triiodothyronine (T(3) ) and E(2) also stimulated the expression of those four genes in LNCaP cells, but co-administration of GH had almost no effect. Finally, we also studied the effects of GH, IGF-I and E(2) , alone or in combination, on LNCaP cell proliferation. Importantly, we demonstrated, for the first time, that although GH and IGF-I alone had no effect on LNCaP cell proliferation, concomitant administration for 96 h revealed a permissive role of GH on IGF-I-induced proliferation. GH also appeared to exert a synergistic effect on E(2) -stimulated LNCaP cell proliferation. Taken together, these findings indicate that GH via GHRs, most likely in concert with gonadal steroids, T(3) , IGF system axis and probably other hormones and growth factors, potentially plays an important role in the mechanisms underlying tumour cell growth in PCa.

Ulanet DB, Ludwig DL, Kahn CR, Hanahan D
Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy.
Proc Natl Acad Sci U S A. 2010; 107(24):10791-8 [PubMed] Free Access to Full Article Related Publications
The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic beta cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti-IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti-IGF-1R therapies.

Kalla Singh S, Tan QW, Brito C, et al.
Insulin-like growth factors I and II receptors in the breast cancer survival disparity among African-American women.
Growth Horm IGF Res. 2010; 20(3):245-54 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: African-American (AA) women with breast cancer are more likely to have advanced disease at diagnosis, higher risk of recurrence and poorer prognosis than Caucasian (CA) women. We have recently shown higher insulin-like growth factor II (IGF-II) expression in paired breast tissue samples from AA women as compared to CA women. IGF-II is a potent mitogen that induces cell proliferation and survival signals through activation of the IGF-I and Insulin receptors (IGF-IR, IR) while IGF-II circulating levels are regulated by cellular uptake through the IGF2 receptor. We hypothesize that differential expression of the IGF1R and IGF2R among AA and CA women potentiates IGF-II mitogenic effects, thus contributing to the health disparity observed between these ethnic groups.
DESIGN: We examined IGF-IR and IGF2R mRNA, protein expression and IGF1R phosphorylation in paired breast tissue samples from AA and CA women by Real Time-PCR, Western blot analysis, immunohistochemistry and ELISA techniques.
RESULTS: Our results showed significantly increased expression of IGF1R in AA normal tissues as compared to CA normal tissues. IGF1R expression was similar between AA normal and malignant tissues, while IGF1R, IRS-1 and Shc phosphorylation was significantly higher in AA tumor samples. Significantly higher levels of IGF2R were found in CA tumor samples as compared to AA tumor samples.
CONCLUSIONS: We conclude that IGF1R and IGF2R differential expression may contribute to the increased risk of malignant transformation in young AA women and to the more aggressive breast cancer phenotype observed among AA breast cancer patients and represent, along with IGF-II, potential therapeutic targets in breast cancer.

Biong M, Gram IT, Brill I, et al.
Genotypes and haplotypes in the insulin-like growth factors, their receptors and binding proteins in relation to plasma metabolic levels and mammographic density.
BMC Med Genomics. 2010; 3:9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Increased mammographic density is one of the strongest independent risk factors for breast cancer. It is believed that one third of breast cancers are derived from breasts with more than 50% density. Mammographic density is affected by age, BMI, parity, and genetic predisposition. It is also greatly influenced by hormonal and growth factor changes in a woman's life cycle, spanning from puberty through adult to menopause. Genetic variations in genes coding for hormones and growth factors involved in development of the breast are therefore of great interest. The associations between genetic polymorphisms in genes from the IGF pathway on mammographic density and circulating levels of IGF1, its binding protein IGFBP3, and their ratio in postmenopausal women are reported here.
METHODS: Samples from 964 postmenopausal Norwegian women aged 55-71 years were collected as a part of the Tromsø Mammography and Breast Cancer Study. All samples were genotyped for 25 SNPs in IGF1, IGF2, IGF1R, IGF2R, IGFALS and IGFBP3 using Taqman (ABI). The main statistical analyses were conducted with the PROC HAPLOTYPE procedure within SAS/GENETICS (SAS 9.1.3).
RESULTS: The haplotype analysis revealed six haploblocks within the studied genes. Of those, four had significant associations with circulating levels of IGF1 or IGFBP3 and/or mammographic density. One haplotype variant in the IGF1 gene was found to be associated with mammographic density. Within the IGF2 gene one haplotype variant was associated with levels of both IGF1 and IGFBP3. Two haplotype variants in the IGF2R were associated with the level of IGF1. Both variants of the IGFBP3 haplotype were associated with the IGFBP3 level and indicate regulation in cis.
CONCLUSION: Polymorphisms within the IGF1 gene and related genes were associated with plasma levels of IGF1, IGFBP3 and mammographic density in this study of postmenopausal women.

Tovar V, Alsinet C, Villanueva A, et al.
IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage.
J Hepatol. 2010; 52(4):550-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway.
METHODS: An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations, and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC.
RESULTS: Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 -resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R (25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p=0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p=0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR<0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivo, A12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis.
CONCLUSIONS: Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials.

Weng CJ, Hsieh YH, Tsai CM, et al.
Relationship of insulin-like growth factors system gene polymorphisms with the susceptibility and pathological development of hepatocellular carcinoma.
Ann Surg Oncol. 2010; 17(7):1808-15 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. The insulin-like growth factors (IGFs) system consists of a group of proteins which may induce cell proliferation and inhibit cell apoptosis through several signal pathways, leading to transformation of normal cells into cancer cells. However, the impact of genetic polymorphisms of the IGFs system on HCC has not been clarified.
METHODS: In this case-control study, a total of 102 HCC patients and 306 age- and gender-matched controls were recruited. The genetic polymorphisms of the IGFs system genes, including IGF-1, IGF-2, IGF-1receptor (IGF-1R), IGF-2R, IGF binding protein (IGFBP-3), and insulin (INS) genes, were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and real-time PCR genotyping analysis.
RESULTS: A significant difference (p = 0.02) between case and control group in the distribution frequency of IGF-2 +3580 polymorphism was observed. Multiple regression model analysis showed that the presence of AA or AG at IGF-2R may exhibit a potential protective effect against hepatitis C [odds ratio (OR) = 0.35, 95% confidence interval (CI) = 0.15-0.82]. The combination of IGF-2 +3580 AA genotype and IGF-2R GG genotype may present a significantly lower risk of HCC (OR = 0.20, 95% CI = 0.05-0.87). Additionally, no polymorphisms of any IGFs system genes were associated with liver-related clinicopathological markers in serum.
CONCLUSIONS: Among IGFs system genes, IGF-2 and IGF-2R gene polymorphisms and combination could be considered as the most important factors contributing to increased susceptibility and pathological development of HCC.

Kishnani PS, Chuang TP, Bali D, et al.
Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease.
Hum Mol Genet. 2009; 18(24):4781-90 [PubMed] Related Publications
Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I) and malignant transformation to hepatocellular carcinoma (HCC) is known to occur in some cases. However, the molecular pathogenesis of tumor development in GSD I is unclear. This study was conducted to systematically investigate chromosomal and genetic alterations in HCA associated with GSD I. Genome-wide SNP analysis and mutation detection of target genes was performed in ten GSD Ia-associated HCA and seven general population HCA cases for comparison. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Intriguingly, simultaneous gain of chromosome 6p and loss of 6q were only seen in GSD Ia HCA (three cases) with one additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (P = 0.012). Expression of IGF2R and LATS1 candidate tumor suppressor genes at 6q was reduced in more than 50% of GSD Ia HCA that were examined (n = 7). None of the GSD Ia HCA had biallelic mutations in the HNF1A gene. These findings give the first insight into the distinct genomic and genetic characteristics of HCA associated with GSD Ia. These results strongly suggest that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and may be in general population. These results also suggest an interesting relationship between GSD Ia HCA and steps to HCC transformation.

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