Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: IGF1 (cancer-related)
Sun Y, Ling CAnalysis of the long non-coding RNA LINC01614 in non-small cell lung cancer.
Medicine (Baltimore). 2019; 98(30):e16437 [PubMed
] Related Publications
The aim of this study was toexplore the long non-coding RNA (lncRNA) expression pattern of non-small cell lung cancer (NSCLC) on a genome-wide scale and investigate their potential biological function in NSCLC.LncRNAs were investigated in 6 pairs of NSCLC and matched adjacent non-tumor lung tissues (NTL) by microarray. A validation cohort was obtained from The Cancer Genome Atlas (TCGA) database and the effect of LINC01614 on diagnosis and prognosis in NSCLC was analyzed. Gene set enrichment analysis (GSEA) was used to predict the potential molecular mechanism of LINC01614, one identified lncRNA.A total of 1392 differentially expressed lncRNAs were identified. LINC01614 was the most aberrantly expressed lncRNA in NSCLC compared with NTL. We confirmed the significantly upregulated LINC01614 in NSCLC patients from TCGA database. Furthermore, in TCGA database, LINC01614 was significantly upregulated in both adenocarcinoma and squamous cell carcinoma. And high expression of LINC01614 indicated poor overall survival of NSCLC patients. A sensitivity of 93% was calculated conditional on a high specificity of 95% for the discrimination of NSCLC tissues from normal tissues. Furthermore, the expression levels of LINC01614 were associated with the stage of tumor, but had no relationship with age and sex. Additionally, GSEA found that LINC01614 might be involved in TGF-β-, P53-, IGF-IR-mediated, Wnt and RTK/Ras/MAPK signaling pathways.lncRNAs may play key roles in the development of NSCLC. LINC01614 is the most aberrantly expressed lncRNA in NSCLC tissues in our experiment and is also significantly differentially expressed in NSCLC patients from TCGA database. LINC01614 could be a prognostic indicator and has the potential to be a diagnostic biomarker of NSCLC.
Chao XL, Wang LL, Liu R, et al.Association between CA repeat polymorphism in IGF1 gene promoter and colorectal cancer risk in a native Chinese population.
Neoplasma. 2019; 2019 [PubMed
] Related Publications
Insulin-like growth factor 1 (IGF1) is implicated in normal cell growth. It has been reported that IGF1 has a mitogenic and anti-apoptotic effect on colorectal cancer cells. However, results of studies on the association between cytosine-adenine (CA) repeat polymorphism in IGF1 gene promoter and colorectal cancer (CRC) risk are inconsistent. We aimed to evaluate the association between CA repeat polymorphism and CRC risk, as well as the relationship with the clinicopathological characteristics of CRC and circulating IGF1 level in a native Chinese population. There were 734 participants who were native Chinese in this case-control study, including 367 CRC cases and 367 age- and sex-matched controls. CA repeat polymorphism was genotyped by PCR and fragment analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated by unconditional logistic regression analysis. Circulating level of IGF1 in cases was significantly higher than that in controls (P = 0.002), particularly in males. Less than 38 CA repeats were associated with decreased CRC risk after adjusting for age and sex (37 versus 38 CA repeats: OR = 0.45; 95%CI = 0.26-0.78), especially in males. (CA)18/19 genotype showed approximately half reduced CRC risk comparing to (CA)19/19 genotype (OR = 0.46; 95%CI = 0.25-0.85). There was a significant association between the sum of CA repeats and degree of differentiation of CRC (P = 0.044). We observed a trend that circulating level of IGF1 in individuals with CA ≤ 38 repeats was lower than that in individuals with CA > 38 repeats with a borderline statistically significance in overall and males. In conclusion, our findings support the possible role of CA repeat polymorphism in CRC risk.
Scirrhous-type gastric cancer (SGC) is one of the most intractable cancer subtypes in humans, and its therapeutic targets have been rarely identified to date. Exploration of somatic mutations in the SGC genome with the next-generation sequencers has been hampered by markedly increased fibrous tissues. Thus, SGC cell lines may be useful resources for searching for novel oncogenes. Here we have conducted whole exome sequencing and RNA sequencing on 2 SGC cell lines, OCUM-8 and OCUM-9. Interestingly, most of the mutations thus identified have not been reported. In OCUM-8 cells, a novel CD44-IGF1R fusion gene is discovered, the protein product of which ligates the amino-terminus of CD44 to the transmembrane and tyrosine-kinase domains of IGF1R. Furthermore, both CD44 and IGF1R are markedly amplified in the OCUM-8 genome and abundantly expressed. CD44-IGF1R has a transforming ability, and the suppression of its kinase activity leads to rapid cell death of OCUM-8. To the best of our knowledge, this is the first report describing the transforming activity of IGF1R fusion genes. However, OCUM-9 seems to possess multiple oncogenic events in its genome. In particular, a novel BORCS5-ETV6 fusion gene is identified in the OCUM-9 genome. BORCS5-ETV6 possesses oncogenic activity, and suppression of its message partially inhibits cell growth. Prevalence of these novel fusion genes among SGC awaits further investigation, but we validate the significance of cell lines as appropriate reagents for detailed genomic analyses of SGC.
Karagiannis AK, Philippou A, Tseleni-Balafouta S, et al.IGF-IEc Expression Is Associated With Advanced Differentiated Thyroid Cancer.
Anticancer Res. 2019; 39(6):2811-2819 [PubMed
] Related Publications
BACKGROUND/AIM: Recent knowledge implicates a differential expression of the insulin-like growth factor-I (IGF-I) mRNA splice variants (i.e., IGF-IEa, IGF-IEb and IGF-IEc) in cancerous tissues, implying possible specific roles of the encoded IGF-I protein isoforms in cancer biology. In particular, there is growing evidence that the IGF-IEc isoform may play a distinct biological role in various types of cancers. The present study investigated whether IGF-IEc expression is associated with a particular type of thyroid cancer.
MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue specimens of different types of thyroid cancers from 92 patients were assessed for IGF-IEc expression by immunohistochemistry. In addition, thyroid cancer biopsies of different TNM staging histological types were evaluated for mRNA expression of the IGF-IEc transcript by real-time polymerase chain reaction (PCR).
RESULTS: From the total number of 92 samples, 2 were anaplastic, 10 medullary, 4 hyperplasias of C-cells, 11 follicular, 5 hurtle cell carcinomas, 2 poorly differentiated, 5 nodular hyperplasias, 1 lymphoma and 52 were papillary thyroid cancers. The age of cancer diagnosis or tumor size did not significantly affect the IGF-IEc expression. Among all types of cancers, IGF-IEc was expressed in papillary differentiated thyroid cancer. Its expression/localization was mainly cytoplasmic and significantly associated with TNM staging and the presence of muscular and capsule cancerous invasion (p<0.05). Similarly, a differential profile was revealed regarding the mRNA expression of the IGF-IEc transcript, that exhibited a higher expression in aggressive compared to the non-aggressive papillary cancers.
CONCLUSION: IGF-IEc isoform expression in thyroid cancer is positively associated with more advanced stages of papillary thyroid cancer.
BACKGROUND: Wilms' tumor is also called nephroblastoma and is the most common pediatric renal cancer. Several genetic and epigenetic factors have been found to account for the development of Wilms' tumor. MiRNAs play important roles in this tumorigenic process. In the present study, we aimed to investigate the role of miR-140-5p in nephroblastoma by identifying its targets, as well as its underlying molecular mechanism of action.
METHODS: The miRNA expression profile of nephroblastoma samples was investigated and the targets of miR-140-5p were predicted and validated using the miRNA luciferase reporter method. Moreover, the roles of miR-140-5p in regulating nephroblastoma cell proliferation, migration and cell cycle were analyzed by the CCK8, migration and flow cytometry assays, respectively. The downstream protein of the direct target of miR-140-5p was also identified.
RESULTS: miR-140-5p was downregulated in Wilms' tumor tissues, whereas in the nephroblastoma cell lines G401 and WT-CLS1 that exhibited high levels of miRNA-140-5p, inhibition of cellular proliferation and metastasis were noted as well as cell cycle arrest at the G1/S phase. TGFBRI and IGF1R were identified as direct target genes for miRNA-140-5p. In addition, SMAD2/3 and p-AKT were regulated by TGFBRI and IGF1R separately and participated in the miRNA-140-5p regulatory network. Ectopic expression of TGFBR1 and IGF-1R could abrogate the inhibitory effect of miR-140-5p.
CONCLUSION: We demonstrated that miRNA-140-5p participates in the progression of Wilms' tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways.
Liu X, Chen H, Hou Y, et al.Adaptive EGF expression sensitizes pancreatic cancer cells to ionizing radiation through activation of the cyclin D1/P53/PARP pathway.
Int J Oncol. 2019; 54(4):1466-1480 [PubMed
] Related Publications
It is well-known that the activation status of the P53, signal transducer and activator of transcription (Stat)3 and nuclear factor (NF)‑κB signaling pathways determines the radiosensitivity of cancer cells. However, the function of these pathways in radiosensitive vs radioresistant cancer cells remains elusive. The present study demonstrated that adaptive expression of epidermal growth factor (EGF) following exposure to ionizing radiation (IR) may induce radiosensitization of pancreatic cancer (PC) cells through induction of the cyclin D1/P53/poly(ADP‑ribose) polymerase pathway. By contrast, adaptively expressed interleukin (IL)‑6 and insulin‑like growth factor (IGF)‑1 may promote radioresistance of PC cells, likely through activation of the Stat3 and NF‑κB pathways. In addition, cyclin D1 and survivin, which are specifically expressed in the G1/S and G2/M phase of the cell cycle, respectively, are mutually exclusive in radiosensitive and radioresistant PC cells, while Bcl‑2 and Bcl‑xL expression does not differ between radiosensitive and radioresistant PC cells. Therefore, adaptively expressed EGF and IL‑6/IGF‑1 may alter these pathways to promote the radiosensitivity of PC cancers. The findings of the present study highlight potential makers for the evaluation of radiosensitivity and enable the development of effective regimens for cancer radiotherapy.
BACKGROUND: Prostate cancer (PCa) is the most common diagnosed malignancy and the second leading cause of cancer-related deaths among men in the United States. High-throughput genotyping has enabled discovery of germline genetic susceptibility variants (herein referred to as germline mutations) associated with an increased risk of developing PCa. However, germline mutation information has not been leveraged and integrated with information on acquired somatic mutations to link genetic susceptibility to tumorigenesis. The objective of this exploratory study was to address this knowledge gap.
METHODS: Germline mutations and associated gene information were derived from genome-wide association studies (GWAS) reports. Somatic mutation and gene expression data were derived from 495 tumors and 52 normal control samples obtained from The Cancer Genome Atlas (TCGA). We integrated germline and somatic mutation information using gene expression data. We performed enrichment analysis to discover molecular networks and biological pathways enriched for germline and somatic mutations.
RESULTS: We discovered a signature of 124 genes containing both germline and somatic mutations. Enrichment analysis revealed molecular networks and biological pathways enriched for germline and somatic mutations, including, the PDGF, P53, MYC, IGF-1, PTEN and Androgen receptor signaling pathways.
CONCLUSION: Integrative genomic analysis links genetic susceptibility to tumorigenesis in PCa and establishes putative functional bridges between the germline and somatic variation, and the biological pathways they control.
Zhang H, Lin J, Hu T, et al.Effect of miR-132 on bupivacaine-induced neurotoxicity in human neuroblastoma cell line.
J Pharmacol Sci. 2019; 139(3):186-192 [PubMed
] Related Publications
BACKGROUND: Local anesthetics (LAs) may generate neurotoxicity in neurons. In the current study, we explored the mechanisms by which microRNA-132 (miR-132) regulated the neurotoxicity of human neuroblastoma cells (SH-SY5Y) induced by bupivacaine (BUP).
METHODS: CCK-8, flow cytometry, EdU detection, qRT-PCR and western blotting were used to explore the cell viability, apoptosis and gene expression, respectively.
RESULTS: In this study, we found that 600 μM BUP dramatically inhibited SH-SY5Y cells viability. In addition, BUP induced cell apoptosis and neurotoxicity via increasing active caspase-3 and cleaved PARP1 levels. More importantly, the level of miR-132 was significantly up-regulated in BUP-treated cells, which was significantly reversed by miR-132 inhibitor. In addition, dual-luciferase assay indicated IGF1R was the directly binding target of miR-132 in cells. Our study further indicated that the level of IGF1R was markedly decreased by BUP interference, while miR-132 inhibitor exerted the opposite effect. Furthermore, BUP induced apoptosis and neurotoxicity in SH-SY5Y cells were attenuated by IGF1, which further confirmed IGF1R was the downstream target of BUP in SH-SY5Y cells.
CONCLUSION: In the present study, miR-132 played important roles in regulating BUP-induced neurotoxicity through IGF1R and may act as a promising molecular target for the treatment of human neurotoxicity induced by BUP.
Li G, Cai L, Zhou LMicroarray gene expression profiling and bioinformatics analysis reveal key differentially expressed genes in clival and sacral chordoma cell lines.
Neurol Res. 2019; 41(6):554-561 [PubMed
] Related Publications
OBJECTIVE: Chordoma is a rare tumor with a certain rate of distant metastasis. Skull base and sacrum are the two most common origin sites. This study tends to identify key differentially expressed genes (DEGs) between classical clival and sacral chordomas, provide new targets for future treatment options of chordomas.
METHODS: The gene expression profiles of GSE95084 and GSE68497 were downloaded from Gene Expression Omnibus database and were analyzed using the limma R package. Function and enrichment analyses of DEGs were performed based on DAVID Database. Protein-protein interaction (PPI) network was constructed using the Cytoscape based on the data collected from STRING online datasets. Hub genes selection and modules analyses of the PPI network were conducted by plugin cytoHubba and MCODE of Cytoscape software, respectively.
RESULT: In total, 728 genes, including 363 up-regulated genes and 365 down-regulated genes were selected as DEGs. Notably, GO analysis showed that both up-regulated and down-regulated DEGs were mainly involved in cell component such as an integral component of the membrane, plasma membrane and extracellular exosome. DEGs were mainly enriched in pathways like Pathways in cancer, PI3K-Akt signaling pathway, Cytokine-cytokine receptor interaction. FYN, ITGB3, ACTN2 and IGF1 were identified as hub genes and they were all involved in focal adhesion signaling pathway. Furthermore, five significant network modules were obtained from the PPI network.
CONCLUSION: This study helps to further understand the molecular characteristics of classic chordomas of two distinct sites. Hub genes FYN, ITGB3, ACTN2, and IGF1, as well as focal adhesion signaling pathway, would be new targets for future treatment options of chordomas.
Kopantzev EP, Kopantseva MR, Grankina EV, et al.Activation of IGF/IGF-IR signaling pathway fails to induce epithelial-mesenchymal transition in pancreatic cancer cells.
Pancreatology. 2019; 19(2):390-396 [PubMed
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BACKGROUND: Pancreatic cancer stromal cells produce various protein factors, which presumably provide cancer cells with drug resistance and may influence their ability to form metastasis via induction of epithelial-mesenchymal transition (ЕМТ). The goal of our project was to study the effects of IGF-I on expression of protein markers of epithelial and mesenchymal differentiation, and on expression of transcriptional regulators of EMT in pancreatic cancer cell lines.
METHODS: We used Western blot analysis to study the expression patterns of epithelial and mesenchymal protein markers in pancreatic cancer cell lines, which have been stimulated with IGF-I for various periods of time. The ELISA technique was employed to determine the concentration of IGF-I in conditioned media. Additionally, the effect of IGF-I on proliferation of pancreatic cancer cells was measured via MTS technique.
RESULTS: We investigated the effect of IGF/IGF-IR signaling pathway activation on expression levels of cell differentiation markers in five pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-2, MiaPaCa-2 and Panc1). The IGF-I stimulation led to phosphorylation of IGF-IR and activation of PI-3K/Akt signaling cascade. At the same time our results reveal that the activation of IGF/IGF-IR signaling pathway in pancreatic cancer cells does not induce a significant shift in cell phenotype towards mesenchymal differentiation and does not induce a decrease in expression levels of epithelial protein markers.
CONCLUSIONS: Our results demonstrate that IGF-I does not function as an effective inductor of EMT in pancreatic cancer cell lines and that stimulation of IGF-I/IGF-IR signaling pathway does not lead to EMT associated changes in cell differentiation.
Al-Gayyar MMH, Bagalagel A, Noor AO, et al.The therapeutic effects of nicotinamide in hepatocellular carcinoma through blocking IGF-1 and effecting the balance between Nrf2 and PKB.
Biomed Pharmacother. 2019; 112:108653 [PubMed
] Related Publications
Insulin growth factor (IGF) family and their receptors play a great role in tumors' development. In addition, IGF-1 enhances cancer progression through regulating cell proliferation, angiogenesis, immune modulation and metastasis. Moreover, nicotinamide is association with protection against cancer. Therefore, we conducted this research to examine the therapeutic effects of nicotinamide against hepatocellular carcinoma (HCC) both in vivo and in vitro through affecting IGF-1 and the balance between PKB and Nrf2. HCC was induced in rats by 200 mg/kg, ip thioacetamide. The rat survival, number and size of tumors and serum α-fetoprotein (AFP) were measured. The gene and protein levels of IGF-1, Nrf2, PKB and JNK-MAPK were assessed in rat livers. In addition, HepG2 cells, human HCC cell lines, were treated with different concentrations of nicotinamide. We found that nicotinamide enhanced the rats' survival and reduced the number and size of hepatic tumors as well as it reduced serum AFP and HepG2 cells survival. Nicotinamide ameliorated HCC-induced reduction in the expression of Nrf2. Moreover, nicotinamide blocked HCC-induced elevation in IGF-1, PKB and JNK-MAPK. In conclusion, nicotinamide produced cytotoxic effects against HCC both in vivo and in vitro. The cytotoxic activity can be explained by inhibition of HCC-induced increased in the expression of IGF-1 and leads to disturbances in the balance between the cell death signal by PKB and MAPK; and the cell survival signal by Nrf2, directing it towards cell survival signals in normal liver cells providing more protection for body against tumor.
Tang D, Wu Q, Yuan Z, et al.Identification of key pathways and gene changes in primary pancreatic stellate cells after cross-talk with pancreatic cancer cells (BXPC-3) using bioinformatics analysis.
Neoplasma. 2019; 2019(3):446-458 [PubMed
] Related Publications
It is well known that as the king of cancer, pancreatic ductal adenocarcinoma (PDAC) has relatively malignant biological behavior and poor prognosis. The interaction between pancreatic stellate cells and PDAC cells promotes the development of PDAC. The aim of this study was to describe gene characteristics in pancreatic stellate cell (PSCs) after cross-talked with BXPC-3 and unravel their underlying mechanisms. The expression profiling analysis of genes in PSCs was completed after co-cultured with primary BXPC-3 for 48h. The Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analysis and gene ontology (GO) analysis were performed, and the differentially expressed genes (DEGs) were identified by Agilent GeneSpring GX program. In total, 1804 DEGs were filtered out in PSCs, including 958 up-regulated genes and 846 downregulated genes. GO analysis showed that the up-regulated DEGs were significantly enriched in biological processes (BP) such as defense response, immune system process and immune response; the down-regulated DEGs were significantly enriched in biological regulation and cytoskeleton organization. KEGG pathway analysis showed that 28 pathways were upregulated and 5 were downregulated. By constructing PPI network, we selected out 10 key genes (IL6，IL8, IL1B, BCL2, CCL2, CSF2, KIT, ICAM1, PTPRC and IGF1) and significant enriched pathways. In conclusion, the current study suggests that the filtered DEGs contribute to our understanding of the molecular mechanisms underlying the interaction between PSCs and pancreatic cancer cells, and might be used as molecular targets to further the study the role of tumor microenvironment in the progression of PDAC.
Shen J, Li L, Yang T, et al.Drug Sensitivity Screening and Targeted Pathway Analysis Reveal a Multi-Driver Proliferative Mechanism and Suggest a Strategy of Combination Targeted Therapy for Colorectal Cancer Cells.
Molecules. 2019; 24(3) [PubMed
] Free Access to Full Article Related Publications
Treatment of colorectal cancer mostly relies on traditional therapeutic approaches, such as surgery and chemotherapy. Limited options of targeted therapy for colorectal cancer narrowly focus on blocking cancer-generic targets VEGFR and EGFR. Identifying the oncogenic drivers, understanding their contribution to proliferation, and finding inhibitors to block such drivers are the keys to developing targeted therapy for colorectal cancer. In this study, ten colorectal cancer cell lines were screened against a panel of protein kinase inhibitors blocking key oncogenic signaling pathways. The results show that four of the 10 cell lines did not respond to any kinase inhibitors significantly, the other six were mildly inhibited by AZD-6244, BMS-754807, and/or dasatinib. Mechanistic analyses demonstrate that these inhibitors independently block the MAP kinase pathway, IR/IGF-1R/AKT pathway, and Src kinases, suggesting a multi-driver nature of proliferative signaling in these cells. Most of these cell lines were potently and synergistically inhibited by pair-wise combinations of these drugs. Furthermore, seven of the 10 cell lines were inhibited by the triple combination of AZD-6244/BMS-754807/dasatinib with IC
Jawiarczyk-Przybyłowska A, Wojtczak B, Whitworth J, et al.Acromegaly associated with GIST, non-small cell lung carcinoma, clear cell renal carcinoma, multiple myeloma, medulla oblongata tumour, adrenal adenoma, and follicular thyroid nodules.
Endokrynol Pol. 2019; 70(2):213-217 [PubMed
] Related Publications
Acromegaly is associated with increased growth hormone (GH) and insulin-like growth factor-I (IGF-I) secretion which may support tumour development and growth. A 68-year-old woman was diagnosed with acromegaly due to typical clinical and hormonal characteristics. While contrast-enhanced MRI at diagnosis did not reveal a pituitary adenoma, a 5-mm lesion was identified on repeat scanning 13 months later. Abdominal and chest CT showed tumours of the stomach, right adrenal gland, and right lung. The CT also showed a hypodense lesion in the liver and heterogeneous echostructure of the thyroid gland with left lobe solid-cystic tumour. Somatostatin receptor scintigraphy revealed increased tracer accumulation in the right thyroid lobe. No tracer accumulation was noted at the location of the other tumours. The resected stomach, adrenal, chest, and thyroid lesions did not show GH secretion. The patient refused pituitary surgery, and her acromegaly is currently well-controlled with somatostatin analogue therapy. A CT scan 19 months later revealed a contrast-enhancing left kidney tumour that was a G1-grade clear cell carcinoma. Four years after the acromegaly diagnosis multiple myeloma were diagnosed with secondary renal amyloidosis. Genetic screening for a paraganglioma gene panel, AIP, MEN1, and CDKN1B mutations were negative. A next-generation cancer panel containing 94 cancer genes did not identify any possible unifying gene abnormality in her germline DNA. Coexistence of acromegaly and numerous other tumours suggests a common aetiology of these disorders. However, no genetic abnormality could be identified with the tests that have been performed.
de Silva HC, Lin MZ, Phillips L, et al.IGFBP-3 interacts with NONO and SFPQ in PARP-dependent DNA damage repair in triple-negative breast cancer.
Cell Mol Life Sci. 2019; 76(10):2015-2030 [PubMed
] Related Publications
Women with triple-negative breast cancer (TNBC) are generally treated by chemotherapy but their responsiveness may be blunted by DNA double-strand break (DSB) repair. We previously reported that IGFBP-3 forms nuclear complexes with EGFR and DNA-dependent protein kinase (DNA-PKcs) to modulate DSB repair by non-homologous end-joining (NHEJ) in TNBC cells. To discover IGFBP-3 binding partners involved in chemoresistance through stimulation of DSB repair, we analyzed the IGFBP-3 interactome by LC-MS/MS and confirmed interactions by coimmunoprecipitation and proximity ligation assay. Functional effects were demonstrated by DNA end-joining in vitro and measurement of γH2AX foci. In response to 20 µM etoposide, the DNA/RNA-binding protein, non-POU domain-containing octamer-binding protein (NONO) and its dimerization partner splicing factor, proline/glutamine-rich (SFPQ) formed complexes with IGFBP-3, demonstrated in basal-like TNBC cell lines HCC1806 and MDA-MB-468. NONO binding to IGFBP-3 was also shown in a cell-free biochemical assay. IGFBP-3 complexes with NONO and SFPQ were blocked by inhibiting EGFR with gefitinib or DNA-PKcs with NU7026, and by the PARP inhibitors veliparib and olaparib, which also reduced DNA end-joining activity and delayed the resolution of the γH2AX signal (i.e. inhibited DNA DSB repair). Downregulation of the long noncoding RNA in NHEJ pathway 1 (LINP1) by siRNA also blocked IGFBP-3 interaction with NONO-SFPQ. These findings suggest a PARP-dependent role for NONO and SFPQ in IGFBP-3-dependent DSB repair and the involvement of LINP1 in the complex formation. We propose that targeting of the DNA repair function of IGFBP-3 may enhance chemosensitivity in basal-like TNBC, thus improving patient outcomes.
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.
Wang F, Li H, Lou Y, et al.Insulin‑like growth factor I promotes adipogenesis in hemangioma stem cells from infantile hemangiomas.
Mol Med Rep. 2019; 19(4):2825-2830 [PubMed
] Related Publications
Infantile hemangiomas (IH) are the most common infantile neoplasms and are characterized by initial proliferation during infancy and subsequent spontaneous regression within the next 5‑10 years, frequently leaving fibrous fat residues. However, the specific mechanisms underlying the differentiation of hemangioma stem cells (HemSCs) into adipocytes are not clear. The purpose of the present study was to investigate the effect of insulin‑like growth factor I (IGF‑1) on HemSCs from patients with IH and to determine the signaling mechanisms involved. Treatment of HemSCs with IGF‑1 led to upregulation of the protein expression levels of peroxisome proliferator‑activated receptor‑γ (PPARγ). By contrast, inhibition of the IGF‑1 receptor (IGF‑1R) or phosphoinositide 3‑kinase (PI3K) activity decreased the expression of PPARγ, in addition to that of CCAAT/enhancer‑binding protein (C/EBP)α, C/EBPβ, and adiponectin. IGF‑1 upregulated the expression of phosphorylated RAC‑α serine/threonine‑protein kinase in IH cells, whereas a specific PI3K inhibitor or IGF‑1R antibody blocked this effect. These results indicated that IGF‑1 is a pro‑proliferative and pro‑lipogenic factor in IH HemSCs. Taken together, these findings indicated that IGF‑1 is able to upregulate PPARγ by activating the IGF‑1R and PI3K pathways, thereby accelerating lipogenesis and enhancing IH HemSC adipogenesis.
BACKGROUND E74-like factor 5 (ELF5) plays a key role in the processes of cell differentiation, apoptosis, and occurrence of tumors. However, the effect of ELF5 on metastasis and invasion in human ovarian cancer remains poorly understood. MATERIAL AND METHODS Quantitative real-time polymerase chain reaction (qPCR) was performed to measure the expression of ELF5. The viability of cells was detected by cell counting kit (CCK-8). Cell apoptosis was tested by flow cytometry. Matrigel plug angiogenesis assay was employed to determine angiogenesis rate. The protein expression levels of vascular endothelial growth factor (VEGF), cleaved caspase-3, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), E-cadherin, N-cadherin, Snail, phosphoinositide 3 kinase (PI3K), phosphorylated (p)-PI3K, tyrosine kinase B (AKT), and phosphorylated (p)-AKT were determined by Western blot. Wound-healing assay and Transwell were used to determine invasion and migration. RESULTS We found that expression of ELF5 was obviously decreased in ovarian cancer cell lines. The cells viability, invasion and metastasis were inhibited by overexpression ELF5. ELF5 suppressed angiogenesis rate and the expression of VEGF. Changes of the expressions of Bcl-2, cleaved caspase-3 and Bax showed that anti-apoptosis ability was improved by ELF5. ELF5 also repressed N-cadherin and Snail and increased E-cadherin. The expressions of p-PI3K and p-AKT were decreased by ELF5. Further study showed that IGF-I reversed the inhibitory effect of ELF5 on growth and metastasis of SKOV3 cells. CONCLUSIONS Overexpression of ELF5 promoted the apoptosis and reduced the migration and invasion of ovarian cancer cells; therefore, it could provide a new approach to gene treatment of ovarian carcinoma.
Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.
BACKGROUND: Many epidemiological studies have suggested that insulin-like growth factor1 (IGF1) gene single-nucleotide polymorphisms (SNPs) may be associated with cancer risk. Among several commonly studied polymorphisms in IGF1 gene, rs2195239 and rs2162679 attracted many attentions. So we perform a meta-analysis to determine potential associations between IGF1 rs2195239 and rs2162679 polymorphisms and cancer risk.
METHODS: We retrieved relevant articles from the PubMed, Embase, and Web of Science databases up to April 30, 2018. Ultimately, thirteen studies were included in the present meta-analysis, which involved 12,515 cases and 19,651 controls. The odd ratios (ORs) and their 95% confidence intervals (CIs) were pooled to estimate the strength of the associations.
RESULTS: rs2195239 reduces the overall cancer risk in homozygote model, as well as reducing cancer risk in Asian populations in allele, homozygote, and recessive models. No significant relationship was found between rs2195239 and breast or pancreatic cancer risk. rs2162679 reduces the overall cancer risk in allele, homozygote, dominant, and recessive models, as well as reducing cancer risk in Asian populations in allele, homozygote, and recessive models.
CONCLUSIONS: IGF1 rs2195239 and rs2162679 were associated with overall cancer risk based on present studies.
BACKGROUND: Osteosarcoma is the most prevalent primary bone malignancy in children and young adults. These tumors are highly metastatic, leading to poor outcome. We previously demonstrated that Cysteine-rich protein 61 (CYR61/CCN1) expression level is correlated to osteosarcoma aggressiveness in preclinical model and in patient tumor samples. The aim of the present study was to investigate the CYR61-induced intracellular mechanisms leading to the acquisition of an invasive phenotype by osteosarcoma cells.
METHODS: Modified murine and human osteosarcoma cell lines were evaluated for cell adhesion, aggregation (spheroid), motility (wound healing assay), phenotypic markers expression (RT-qPCR, western blot). Cell-derived xenograft FFPE samples and patients samples (TMA) were assessed by IHC.
RESULTS: CYR61 levels controlled the expression of markers related to an Epithelial-mesenchymal transition (EMT)-like process, allowing tumor cells to migrate acquiring a competent morphology, and to be able to invade the surrounding stroma. This phenotypic shift indeed correlated with tumor grade and aggressiveness in patient samples and with the metastatic dissemination potential in cell-derived xenograft models. Unlike EGFR or PDGFR, IGF1Rβ levels correlated with CYR61 and N-cadherin levels, and with the aggressiveness of osteosarcoma and overall survival. The expression levels of IGF1Rβ/IGF1 axis were controlled by CYR61, and anti-IGF1 neutralizing antibody prevented the CYR61-induced phenotypic shift, aggregation, and motility abilities.
CONCLUSIONS: Taken together, our study provides new evidence that CYR61 acts as a key inducing factor in the metastatic progression of osteosarcoma by playing a critical role in primary tumor dissemination, with a process associated with IGF1/IGFR stimulation. This suggests that CYR61 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma, in correlation with IGF1/IGFR pathway.
Shu S, Liu X, Xu M, et al.MicroRNA-320a acts as a tumor suppressor in endometrial carcinoma by targeting IGF-1R.
Int J Mol Med. 2019; 43(3):1505-1512 [PubMed
] Related Publications
Dysregulation of microRNAs (miRs) is implicated in the carcinogenesis of various types of malignant tumor by manipulating cell growth and apoptosis. Abnormal expression of miR‑320a is involved in tumorigenesis of many types of cancer. The potential association of miR‑320a and the possible regulatory mechanisms in endometrial carcinoma is rarely elucidated. In the present study, it was demonstrated that miR‑320a expression was decreased in endometrial carcinoma tissues and cell lines. The present results also indicated that overexpression of miR‑320a suppressed cell proliferation through inducing G2/M phrase arrest and apoptosis. Insulin‑like growth factor receptror‑1 (IGF‑1R) was verified to be the potential target of miR‑320a by computational analysis and luciferase reporter assays. In addition, overexpression of miR‑320a reduced endogenous IGF‑1R expression in cells. Furthermore, it was demonstrated that upregulation of miR‑320a inhibited phosphorylated (p)‑protein kinase B and p‑mechanistic target of rapamycin activation and promoted B cell lymphoma‑2‑associated death promoter expression. Reintroduction of IGF‑1R into miR‑320a‑overexpressed cells antagonized the impact of miR‑320a on its downstream protein, which demonstrated that the tumor suppressive role of miR‑320a in endometrial carcinoma is exerted by the signal pathway mediated by IGF‑1R. It was therefore concluded that miR‑320a served an anti‑tumor role on endometrial carcinoma through the regulation of IGF‑1R, and miR‑320a may be used as the target for the gene therapy of endometrial carcinoma.
Kalledsøe L, Dragsted LO, Hansen L, et al.The insulin-like growth factor family and breast cancer prognosis: A prospective cohort study among postmenopausal women in Denmark.
Growth Horm IGF Res. 2019; 44:33-42 [PubMed
] Related Publications
OBJECTIVE: Circulating levels of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have been associated with breast cancer (BC) risk. The evidence in relation to BC prognosis is limited. We aimed to evaluate the association between pre-diagnostic serum levels of IGF-I, IGF-II, IGFBP-2, IGFBP-3 and BC prognosis (i.e. recurrence, BC specific mortality and all-cause mortality) among women diagnosed with BC. We hypothesized that higher serum levels of IGFs and IGFBPs were associated with poor BC prognosis and that the associations were modified by estrogen receptor (ER) status.
DESIGN: From the Danish Diet, Cancer and Health cohort, 412 postmenopausal women diagnosed with incident BC within 5 years of cohort baseline (1993-1997) were identified. Baseline serum samples were analyzed for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Follow-up was carried out through 2014 by linkage to national Danish registries. Exposures were related to BC prognosis by Cox Proportional Hazard models; effect modification by ER status was investigated and sensitivity analyses by follow-up time were made.
RESULTS: During a median of 15 years, 106 women experienced recurrence and 172 died (118 due to BC). Overall, no associations were observed between IGF-I, IGF-II, IGFBP-2, IGFBP-3 and BC prognosis and no effect modification by ER status was observed. However, higher levels of IGF-II were associated with higher BC specific mortality [Hazard Ratio (HR) (95% Confidence Intervals (CI)): 1.43 (1.01-2.04)] within 10 years of follow-up. Likewise, higher levels of IGFBP-2 were associated with higher BC specific mortality [HR (95% CI): 1.87 (1.19-2.94)] within 5 years of follow-up. In contrast, higher levels of IGFBP-3 were associated with lower risk of recurrence [HR (95% CI): 0.76 (0.60-0.97)] at 5 years of follow-up and BC specific mortality [HR (95% CI): 0.80 (0.65-0.98)] within 10 years of follow-up.
CONCLUSIONS: The present study did not support an association between higher serum levels of IGFs, IGFBPs and adverse BC prognosis. However, it is possible that the role of the IGF family in the etiology of the 5-10 year BC prognosis is different from that of longer-term BC prognosis.
BACKGROUND AND OBJECTIVE: Insulin-like growth factor 1 (IGF1) gene three prime untranslated region (3'-UTR) polymorphisms have been reported to be associated with cancer risk. However, the conclusions of the relevant studies are not consistent. The present meta-analysis evaluates the relationship between IGF1 gene 3'-UTR polymorphisms (rs5742714, rs6214, and rs6220) and cancer risk.
METHODS: Articles regarding the relationship between IGF1 rs5742714, rs6214, and rs6220 polymorphisms and cancer risk were selected by searching the PubMed, Embase, and Web of Science databases before April 30, 2018. Altogether, we obtained 34 case-controlled studies from 20 articles, including 21,568 cases and 31,199 controls. The strength of associations was quantified using odds ratios (ORs) and the corresponding 95% confidence intervals (CIs).
RESULTS: In the present meta-analysis, no significant associations were detected between rs5742714, rs6214, and rs6220 and overall cancer risk. Thus, in stratified analyses, we found that rs6214 was associated with a significantly reduced risk of breast cancer under the allele, heterozygote, and dominant models (A vs G: OR, 0.94, 95% CI,0.88-1.00, P = .044; GA vs GG: OR, 0.88, 95% CI, 0.80-0.97, P = .012; AA + GA vs GG: OR, 0.89, 95% CI, 0.81-0.97, P = .011), as well as pancreatic cancer under the recessive model (AA vs GA + GG: OR, 0.68, 95% CI,0.53-0.87, P = .003). Also, rs6220 was associated with a significantly increased risk of breast cancer under the homozygote model (GG vs AA: OR, 1.23, 95% CI, 1.02-1.48, P = .031). In addition, rs6220 was found to increase overall cancer risk among Caucasians under the allele model (G vs A: OR, 1.06, 95% CI, 1.00-1.13, P = .043).
CONCLUSIONS: In this meta-analysis, we investigated and reviewed the relationship between IGF1 gene 3'-UTR polymorphisms (rs5742714, rs6214, and rs6220) and cancer risk based on present epidemiological studies. Further studies are needed to draw more precise conclusions in the future.
Li Z, Lu Q, Zhu D, et al.Lnc-SNHG1 may promote the progression of non-small cell lung cancer by acting as a sponge of miR-497.
Biochem Biophys Res Commun. 2018; 506(3):632-640 [PubMed
] Related Publications
Lnc-SNHG1 (small nucleolar RNA host gene 1) is considered an important regulating factor in several types of cancers. However, the biological functions and underlying molecular mechanisms in which lnc-SNHG1 is involved in non-small cell lung cancer (NSCLC) still need to be explored. In this study, we investigated the detailed effects and possible molecular mechanisms. The transcript level of lnc-SNHG1 was higher in lung adenocarcinoma specimens and NSCLC cell lines than in noncancer tissue and cells. The level of expression was positively correlated with invasiveness and was negatively correlated with the level of miR-497 in vivo and in vitro. In exploring the regulatory mechanism, we found that lnc-SNHG1 might modulate tumor growth by sponging miR-497. The inhibitory effect of si-lnc-SNHG1 on NSCLC cell proliferation, migration and invasion could be rescued by miR-497 inhibition, while the overexpression of miR-497 could reverse the effect of lnc-SNHG1 overexpression. Furthermore, our study demonstrated that the lnc-SNHG1 regulated the expression of the insulin-like growth factor 1 receptor (IGF1-R) by acting as a sponge of miR-497 in NSCLC. lnc-SNHG1 could be a novel biomarker as well as a curative target.
The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.
Karimabad MN, Mahmoodi M, Jafarzadeh A, et al.Molecular Targets, Anti-cancer Properties and Potency of Synthetic Indole-3-carbinol Derivatives.
Mini Rev Med Chem. 2019; 19(7):540-554 [PubMed
] Related Publications
The indole-3-carbinol (I3C) displays anti-cancer/proliferative activities against human cancer cells. Cellular proliferation is an event associated with the progress and its continuation. This manifest is described by variation in expression and/or functions of genes that are related with cell cycle relevant proteins. The constitutive activation of several signal transduction pathways stimulates cells proliferation as well. The immediate stages in cancer development are accompanied by a fibrogenic response and the progression of the hypoxic environment is in favor of survival and proliferatory functions of cancer stem cells. A main part for prevention of in cancer cells death may manifest through altering cell metabolism. Cellular proliferation and metastasis are reported to be supported with increased generation of responsible hormones (in hormone dependent malignancies), and further promotion the angiogenesis, with epithelial to mesenchymal transition. This may be facilitated by progression of autophagy phenomenon, as well as via taking cues from neighboring stromal cells. Several signaling pathways in association with various factors specific for cellular viability, including hypoxia inducible factor 1, NF-κB, insulin-like growth factor 1 (IGF-1) receptor, Human foreskin fibroblasts (HFF-1), phosphoinositide 3 kinase/Akt, Wnt, cell cycle related protein, with androgen and estrogen receptor signaling are reported to be inhibited by I3C. These evidences, in association with bioinformatics data represent very important information for describing signaling pathways in parallel with molecular targets that may serve as markers for early diagnosis and/or critical targets for designing and development of novel therapeutic regimes alone or combined with drugs, to prevent tumor formation and further progression. In particular, I3C and DIM have been extensively investigated for their importance against numbers human cancers both in vitro and in vivo. We aimed the present manuscript, current study, to review anticancer properties and the miscellaneous mechanisms underlying the antitumorigenicity in an in-depth study for broadening the I3C treating marvel.
Sin STK, Li Y, Liu M, et al.TROP-2 exhibits tumor suppressive functions in cervical cancer by dual inhibition of IGF-1R and ALK signaling.
Gynecol Oncol. 2019; 152(1):185-193 [PubMed
] Related Publications
OBJECTIVE: Inactivation of tumor suppressor genes promotes initiation and progression of cervical cancer. This study aims to investigate the tumor suppressive effects of TROP-2 in cervical cancer cells and to explain the underlying mechanisms.
METHODS: The tumor suppressive functions of TROP-2 in cervical cancer cells were examined by in vitro and in vivo tumorigenic functional assays. Downstream factors of TROP-2 were screened using Human Phospho-Receptor Tyrosine Kinase Array. Small molecule inhibitors were applied to HeLa cells to test the TROP-2 effects on the oncogenicity of IGF-1R and ALK. Protein interactions between TROP-2 and the ligands of IGF-1R and ALK were detected via immunoprecipitation assay and protein-protein affinity prediction.
RESULTS: In vitro and in vivo functional assays showed that overexpression of TROP-2 significantly inhibited the oncogenicity of cervical cancer cells; while knockdown of TROP-2 exhibited opposite effects. Human Phospho-Receptor Tyrosine Kinase Array showed that the activity of IGF-1R and ALK was stimulated by TROP-2 knockdown. Small molecule inhibitors AG1024 targeting IGF-1R and Crizotinib targeting ALK were treated to HeLa cells with and without TROP-2 overexpression, and results from cell viability and migration assays indicated that the oncogenicity of vector-transfected cells was repressed to a greater extent by the inhibition of either IGF-1R or ALK than that of the TROP-2-overexpressed cells. Immunoprecipitation assay and protein-protein affinity prediction suggested protein interactions between TROP-2 and the ligands of IGF-1R and ALK.
CONCLUSIONS: Collectively, our results support that TROP-2 exhibits tumor suppressor functions in cervical cancer through inhibiting the activity of IGF-1R and ALK.
Geng Y, Sui C, Xun Y, et al.MiRNA-99a can regulate proliferation and apoptosis of human granulosa cells via targeting IGF-1R in polycystic ovary syndrome.
J Assist Reprod Genet. 2019; 36(2):211-221 [PubMed
] Article available free on PMC
after 01/02/2020 Related Publications
PURPOSE: We aimed to evaluate the regulation of miR-99a to the biological functions of granulosa cells in polycystic ovary syndrome (PCOS) via targeting IGF-1R.
METHODS: We collected aspirated follicular fluid in both patients with and without PCOS. Granulosa cells (GCs) were isolated through Percoll differential centrifugation to detect both miR-99a and IGF-1R expressions. We further transfected COV434 cells with miR-99a mimics to establish a miRNA-99a (miR-99a) overexpression model. We explored the regulation of miR-99a to the proliferation and apoptosis of human GCs via IGF-1R in COV434. The effect of different insulin concentrations on miR-99a expression was also evaluated.
RESULTS: MiR-99a was significantly downregulated while IGF-1R was upregulated in patients with PCOS. MiR-99a can regulate IGF-1R on a post-transcriptional level. After transfection of miR-99a mimics, the proliferation rate was decreased and apoptosis rate was increased significantly in COV434. Exogenous insulin-like growth factor 1 (IGF-1) treatment could reverse the effect of miR-99a. MiR-99a was negatively and dose-dependently regulated by insulin in vitro.
CONCLUSIONS: MiR-99a expression was downregulated in patients with PCOS, the degree of which may be closely related to insulin resistance and hyperinsulinemia. MiR-99a could attenuate proliferation and promote apoptosis of human GCs through targeting IGF-1R, which could partly explain the abnormal folliculogenesis in PCOS.
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
] Article available free on PMC
after 01/02/2020 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.