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.

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

• 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.

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.