Role of LncRNA H19 in The Regulation of IGF-1R Expression

NCT04767750 | Completed

• 1 other identifier: MS.20.10.26
• Study Type: observational
• Target: 101
• Locations: 1 country
• Sites: 2

Brief Summary

Hepatocellular carcinoma (HCC) is a common cancer that poses a heavy economic burden on the healthcare system. In Egypt, it is the most common cause of mortality and morbidity-related cancer. Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia. Cancer and type II diabetes (T2DM), the world's two most prevalent diseases, share many overlapping risk factors and predisposing pathological conditions. The exact mechanisms linking those two diseases are yet to be fully understood. In this study, the investigators aim to assess the relationship between Long Non-Coding RNA (lncRNA) H19 and Insulin-Like Growth Factor 1 Receptor (IGF-1R) mRNA gene expressions in the blood samples of HCC \& T2DM patients to investigate the probability of the presence of a pathophysiological link between HCC and DM that may become a therapeutic target for both diseases. To the investigator's knowledge, there is currently no human research study investigating both H19 and IGF-1R in both DM and cancer.

Conditions

Hepatocellular Carcinoma; Type 2 Diabetes; Cancer

Keywords

LncRNA H19; IGF-1R

Outcome Measures

Primary Outcomes (1)

• Measurement of the gene expression levels of LncRNA H19 & IGF-1R mRNA, normalized to the housekeeping gene GAPDH expression level, in HCC and T2DM in comparison with healthy controls using Real-Time Quantitative PCR (by the 2^-ΔΔCT method).

  To assess if there is a correlation between lncRNA H19 and IGF-1R mRNA gene expressions in the blood samples of HCC \& T2DM patients to investigate the probability of the presence of a pathophysiological link between HCC and DM: * To measure the IGF-1R mRNA and lncRNA H19 expression levels in HCC \& T2DM patients in comparison with healthy controls. * To investigate whether lncRNA H19 and IGF-1R mRNA expression levels affect one another. * To compare IGF-1R and lncRNA H19 expression levels in HCC associated with T2DM patients in contrast with sole affection with HCC or T2DM.

  baseline

Study Arms (4)

HCC patients

Measure lncRNA H19 and IGF-1R mRNA gene expression levels in the collected blood samples.

Other: Blood sample collection

T2DM patients

Measure lncRNA H19 and IGF-1R mRNA gene expression levels in the collected blood samples.

Other: Blood sample collection

HCC & T2DM patients

Measure lncRNA H19 and IGF-1R mRNA gene expression levels in the collected blood samples.

Other: Blood sample collection

Controls

Measure lncRNA H19 and IGF-1R mRNA gene expression levels in the collected blood samples.

Other: Blood sample collection

Interventions

Blood sample collection OTHER

5ml of peripheral blood samples will be collected into tubes containing EDTA from all subjects and the following procedures will be performed: * Peripheral blood mononuclear cells (PBMCs) will be isolated from blood samples. * Total RNA extraction from PBMCs by Trizol reagent and spin column. * Reverse transcription to cDNA. * The expression levels of lncRNA H19, IGF-1R mRNA and GAPDH gene (control gene) will be determined by Real-Time Quantitative PCR

Controls; HCC & T2DM patients; HCC patients; T2DM patients

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This case-control study will be conducted in the Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University. Blood samples will be obtained from 24 HCC patients and 24 HCC \& T2DM patients at the Gastroenterology Center, Mansoura University as well as from 26 T2DM patients at the Specialized Medical Hospital, Mansoura University in the period from December 2020 to December 2021. The study will include 101 patients divided into 4 groups: Group I: 24 HCC patients Group II: 26 T2DM patients Group III: 24 HCC \& T2DM patients Group IV: 27 age and gender-matched healthy control volunteers. Written informed consent will be obtained from all individuals.

You may qualify if:

• \- Patients aged 40 years or older with a confirmed diagnosis of HCC through triphasic CT and/or dynamic MRI (European Association for the Study of the Liver, 2012).

You may not qualify if:

• Patients who underwent previous cancer-directed treatment (radiation and/or chemotherapy).
• Patients with any other systemic disease (Renal disease, other primary tumors).
• T2DM cases (group II):
• \- Clinically diagnosed T2DM patients aged 40 years or older frequenting Mansoura Specialized Medical Hospital.
• Patients with previous or current malignancies.
• Patients with diabetic complications (Diabetic retinopathy, neuropathy, nephropathy).
• Patients with other systemic diseases.
• HCC \& T2DM cases (group III):
• \- Patients aged 40 years or older with a confirmed diagnosis of HCC through triphasic CT and/or dynamic MRI and who are clinically diagnosed to have T2DM.
• Patients who underwent previous cancer-directed treatment (radiation and/or chemotherapy).
• Patients with any other systemic disease.
• Controls (group IV):
• Apparently healthy, age, and gender-matched subjects.
• No history of malignant disease, diabetes, or HCV.

Sponsors & Collaborators

• Mansoura University: lead

Study Sites (2)

Gastroenterology Center, Mansoura University

Al Mansurah, Dakahliya, 35516, Egypt

Location

Specialized Medical Hospital, Mansoura University

Al Mansurah, Dakahliya, 35516, Egypt

Location

Related Publications (21)

• Chen B, Li J, Chi D, Sahnoune I, Calin S, Girnita L, Calin GA. Non-Coding RNAs in IGF-1R Signaling Regulation: The Underlying Pathophysiological Link between Diabetes and Cancer. Cells. 2019 Dec 14;8(12):1638. doi: 10.3390/cells8121638.

  PMID: 31847392 BACKGROUND

• Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM. The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res. 2008 Oct 15;14(20):6364-70. doi: 10.1158/1078-0432.CCR-07-4879.

  PMID: 18927274 BACKGROUND

• Ding J, Li C, Tang J, Yi C, Liu JY, Qiu M. Higher Expression of Proteins in IGF/IR Axes in Colorectal Cancer is Associated with Type 2 Diabetes Mellitus. Pathol Oncol Res. 2016 Oct;22(4):773-9. doi: 10.1007/s12253-016-0065-6. Epub 2016 May 2.

  PMID: 27138191 BACKGROUND

• Fabbri M, Girnita L, Varani G, Calin GA. Decrypting noncoding RNA interactions, structures, and functional networks. Genome Res. 2019 Sep;29(9):1377-1388. doi: 10.1101/gr.247239.118. Epub 2019 Aug 21.

  PMID: 31434680 BACKGROUND

• Farzi-Molan A, Babashah S, Bakhshinejad B, Atashi A, Fakhr Taha M. Down-regulation of the non-coding RNA H19 and its derived miR-675 is concomitant with up-regulation of insulin-like growth factor receptor type 1 during neural-like differentiation of human bone marrow mesenchymal stem cells. Cell Biol Int. 2018 Aug;42(8):940-948. doi: 10.1002/cbin.10960. Epub 2018 Mar 30.

  PMID: 29512257 BACKGROUND

• Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 1;136(5):E359-86. doi: 10.1002/ijc.29210. Epub 2014 Oct 9.

  PMID: 25220842 BACKGROUND

• Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018 Mar 31;391(10127):1301-1314. doi: 10.1016/S0140-6736(18)30010-2. Epub 2018 Jan 5.

  PMID: 29307467 BACKGROUND

• Ghazal S, McKinnon B, Zhou J, Mueller M, Men Y, Yang L, Mueller M, Flannery C, Huang Y, Taylor HS. H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis. EMBO Mol Med. 2015 Aug;7(8):996-1003. doi: 10.15252/emmm.201505245.

  PMID: 26089099 BACKGROUND

• Global Burden of Disease Liver Cancer Collaboration; Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, Al-Raddadi R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele TA, Barac A, Bensenor I, Berhane A, Bhutta Z, Castillo-Rivas J, Chitheer A, Choi JY, Cowie B, Dandona L, Dandona R, Dey S, Dicker D, Phuc H, Ekwueme DU, Zaki MS, Fischer F, Furst T, Hancock J, Hay SI, Hotez P, Jee SH, Kasaeian A, Khader Y, Khang YH, Kumar A, Kutz M, Larson H, Lopez A, Lunevicius R, Malekzadeh R, McAlinden C, Meier T, Mendoza W, Mokdad A, Moradi-Lakeh M, Nagel G, Nguyen Q, Nguyen G, Ogbo F, Patton G, Pereira DM, Pourmalek F, Qorbani M, Radfar A, Roshandel G, Salomon JA, Sanabria J, Sartorius B, Satpathy M, Sawhney M, Sepanlou S, Shackelford K, Shore H, Sun J, Mengistu DT, Topor-Madry R, Tran B, Ukwaja KN, Vlassov V, Vollset SE, Vos T, Wakayo T, Weiderpass E, Werdecker A, Yonemoto N, Younis M, Yu C, Zaidi Z, Zhu L, Murray CJL, Naghavi M, Fitzmaurice C. The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol. 2017 Dec 1;3(12):1683-1691. doi: 10.1001/jamaoncol.2017.3055.

  PMID: 28983565 BACKGROUND

• Hashad D, Elbanna A, Ibrahim A, Khedr G. Evaluation of the Role of Circulating Long Non-Coding RNA H19 as a Promising Novel Biomarker in Plasma of Patients with Gastric Cancer. J Clin Lab Anal. 2016 Nov;30(6):1100-1105. doi: 10.1002/jcla.21987. Epub 2016 May 17.

  PMID: 27184562 BACKGROUND

• Huang JY, Wang SY, Lin Y, Yi HC, Niu JJ. The Diagnostic Performance of lncRNAs from Blood Specimens in Patients with Hepatocellular Carcinoma: A Meta-Analysis. Lab Med. 2021 Jan 4;52(1):64-73. doi: 10.1093/labmed/lmaa050.

  PMID: 32700735 BACKGROUND

• Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971. doi: 10.1155/2014/437971. Epub 2014 Sep 21.

  PMID: 25328522 BACKGROUND

• European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012 Apr;56(4):908-43. doi: 10.1016/j.jhep.2011.12.001. No abstract available.

  PMID: 22424438 BACKGROUND

• Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, Galun E. The H19 non-coding RNA is essential for human tumor growth. PLoS One. 2007 Sep 5;2(9):e845. doi: 10.1371/journal.pone.0000845.

  PMID: 17786216 BACKGROUND

• Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012 Feb 16;12(3):159-69. doi: 10.1038/nrc3215.

  PMID: 22337149 BACKGROUND

• Rashed WM, Kandeil MAM, Mahmoud MO, Ezzat S. Hepatocellular Carcinoma (HCC) in Egypt: A comprehensive overview. J Egypt Natl Canc Inst. 2020 Jan 16;32(1):5. doi: 10.1186/s43046-020-0016-x.

  PMID: 32372179 BACKGROUND

• Raveh E, Matouk IJ, Gilon M, Hochberg A. The H19 Long non-coding RNA in cancer initiation, progression and metastasis - a proposed unifying theory. Mol Cancer. 2015 Nov 4;14:184. doi: 10.1186/s12943-015-0458-2.

  PMID: 26536864 BACKGROUND

• Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019 Apr 11;380(15):1450-1462. doi: 10.1056/NEJMra1713263. No abstract available.

  PMID: 30970190 BACKGROUND

• Ye Y, Guo J, Xiao P, Ning J, Zhang R, Liu P, Yu W, Xu L, Zhao Y, Yu J. Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma. Cancer Lett. 2020 Jan 28;469:310-322. doi: 10.1016/j.canlet.2019.11.001. Epub 2019 Nov 6.

  PMID: 31705929 BACKGROUND

• Zhang N, Geng T, Wang Z, Zhang R, Cao T, Camporez JP, Cai SY, Liu Y, Dandolo L, Shulman GI, Carmichael GG, Taylor HS, Huang Y. Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia. JCI Insight. 2018 May 17;3(10):e120304. doi: 10.1172/jci.insight.120304. eCollection 2018 May 17.

  PMID: 29769440 BACKGROUND

• Zhao M, Wang H, Chen J, Xi Y, Wang F, Huo C, Li W, Chu Y, Xu P, Huang Q, Bu S. Expression of long non-coding RNA H19 in colorectal cancer patients with type 2 diabetes. Arch Physiol Biochem. 2021 Jun;127(3):228-234. doi: 10.1080/13813455.2019.1628068. Epub 2019 Jun 22.

  PMID: 31232113 BACKGROUND

Related Links

• Abudeif, A. (2019) 'Epidemiology and Risk Factors of Hepatocellular Carcinoma in Egypt', Sohag Medical Journal. Sohag University; Faculty of Medicine, 23(3), pp. 8-12.

Biospecimen

Retention: SAMPLES WITH DNA

5ml of peripheral blood samples will be collected

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Diabetes Mellitus, Type 2; Neoplasms; Insulin-Like Growth Factor I, Resistance To

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Officials

• Noura MS Shehabeldin, M.B.B.Ch

  Faculty of Medicine, Mansoura University.

  PRINCIPAL INVESTIGATOR

• Mohamed AA Zahran, M.D.

  Faculty of Medicine, Mansoura University.

  STUDY DIRECTOR

• Heba K Mohamed, M.D.

  Faculty of Medicine, Mansoura University.

  STUDY CHAIR

• Nora M Hussein, M.D.

  Faculty of Medicine, Mansoura University.

  STUDY CHAIR

• Ahmed Shehta, M.D.

  Gastroenterology Center, Mansoura University

  STUDY CHAIR

• Helmy Ezzat, M.D.

  Gastroenterology Center, Mansoura University

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2020
• First Posted: February 23, 2021
• Study Start: January 1, 2020
• Primary Completion: January 30, 2022
• Study Completion: April 4, 2022
• Last Updated: April 7, 2022

Record last verified: 2021-02

Locations

EG (2)