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

Cancer Clinical Trial

Official title:

Role of LncRNA H19 in The Regulation of IGF-1R Expression: A Possible Association Between Type 2 Diabetes and Hepatocellular Carcinoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04767750
• Other study ID #: MS.20.10.26
• Status: Completed
• Start date: January 1, 2020
• Est. completion date: April 4, 2022

Study information

• Verified date: February 2021
• Source: Mansoura University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Description:

Hepatocellular carcinoma (HCC) is a common cancer that poses a heavy economic burden on the healthcare system. It represents the fourth and sixth most common cancer in Egypt and worldwide respectively. Globally, HCC is the fourth most common cause of death from cancer. It was estimated to be responsible for nearly 9.1% of the total deaths in 2012 (746,000 deaths). In Egypt, it is the most common cause of cancer-related mortality, and morbidity (32.35% of the total cancer deaths, mortality data were derived from the World Health Organization (WHO)). The leading risk factor in developing HCC in Egypt is hepatitis C virus (HCV).

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, which may be caused by insufficient insulin secretion, insulin resistance, or augmented glucagon production. Cancer and type II diabetes (T2DM), The world's two most prevalent diseases, share many overlapping risk factors and predisposing pathological conditions. Although the T2DM-cancer co-existence has been noted for many decades, the exact mechanisms linking these diseases are yet to be fully understood.

Insulin-Like Growth Factor-1 Receptor (IGF-1R) is a member of the insulin and IGF family. It coordinates a complex downstream signaling network through which it plays essential roles in the regulation of cell growth, proliferation, and survival as well as in glucose homeostasis. IGF-1R plays a crucial role in many tumor-related courses, such as tumor growth and metastasis in addition to drug resistance. The IGF-1R dysregulated signaling pathways in cancer and DM have been reported to be controlled at different levels by non-coding RNAs.

Non-coding RNAs (ncRNAs) are a large category of RNAs that usually do not participate in protein encoding but have a wide range of biological functions through regulation of protein expression and functions. The two most researched classes of ncRNAs are microRNAs (miRNAs) and the long non-coding RNAs (lncRNAs). H19 is a lncRNA that is found to be overexpressed in many solid tumors including HCC. The relationship between H19 and IGF-1R expression levels in addition to the dysregulation of H19 in DM are still inconsistent in literature, warranting further investigations. Ghazal et al. noted that H19 levels are directly proportional to IGF-1R expression levels in women with endometriosis (Ghazal et al., 2015). This is conflicting with Farzi-Molan et al. who remarked the reverse relation between IGF-1R & H19 during the differentiation of Bone Marrow Mesenchymal Stem Cells (BMSCs) to neural cells

Recruitment information / eligibility

• Status: Completed
• Enrollment: 101
• Est. completion date: April 4, 2022
• Est. primary completion date: January 30, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 40 Years and older

Eligibility

• HCC cases (group I):

Inclusion criteria:

• 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).

Exclusion criteria:

• 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):

Inclusion criteria:

• Clinically diagnosed T2DM patients aged 40 years or older frequenting Mansoura Specialized Medical Hospital.

Exclusion criteria:

• Patients with previous or current malignancies.

• Patients with diabetic complications (Diabetic retinopathy, neuropathy, nephropathy).

• Patients with other systemic diseases.

• HCC & T2DM cases (group III):

Inclusion criteria:

• 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.

Exclusion criteria:

• 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.

Related Conditions & MeSH terms

• Cancer
• Carcinoma
• Carcinoma, Hepatocellular
• Diabetes Mellitus, Type 2
• Hepatocellular Carcinoma
• Type 2 Diabetes

Intervention

Other:
• Blood sample collection
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

Locations

Country	Name	City	State
Egypt	Gastroenterology Center, Mansoura University	Mansoura	Dakahliya
Egypt	Specialized Medical Hospital, Mansoura University	Mansoura	Dakahliya

Sponsors (1)

Lead Sponsor	Collaborator
Mansoura University

Country where clinical trial is conducted

Egypt, 

References & 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). pii: E1638. doi: 10.3390/cells8121638. Review. — View Citation

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. Review. — View Citation

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. — View Citation

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. Erratum in: J Hepatol. 2012 Jun;56(6):1430. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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, Fürst 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, Topór-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. — View Citation

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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. — View Citation

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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. Review. — View Citation

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. — View Citation

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Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019 Apr 11;380(15):1450-1462. doi: 10.1056/NEJMra1713263. Review. — View Citation

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. — View Citation

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). pii: 120304. doi: 10.1172/jci.insight.120304. eCollection 2018 May 17. — View Citation

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. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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^-??CT 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

External 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.
•   Wang, R., Li, K., Xie, Z., Wang, B., Dai, Y., Chen, J.,Ye, Y. (2020) 'Formononetin Induces Apoptosis of PC-3 Human Prostate Cancer Cells via Regulating Long Noncoding RNA H19 and the Mitochondrial Apoptosis Pathway Ruyue', Pharmacogn. Magazine