Impact of circ-0000221 in the Pathogenesis of Hepatocellular via Modulation of miR-661-PTPN11 mRNA Axis.

Marwa Matboli,Hesham Elghazaly,Mohmed Kamal Hassan,Hebatallah Said Aly,Mahmoud A Ali,Waheba Elsayed,Sherif El-Khamisy,Sara H A Agwa,Reham Atteya,Mohamed Tarek Mansour,Mahmoud El Meteini

doi:10.3390/pharmaceutics14010138

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in Egypt. A deep understanding of the molecular events occurring in HCC can facilitate the development of novel diagnostic and/or therapeutic approaches. In the present study, we describe a novel axis of hsa-circ-0000221–miR-661–PTPN11 mRNA proposed by in silico and in vitro analysis and its role in HCC pathogenesis. We observe a reduction in the expression levels of hsa-circ-0000221 and PTPN11 mRNA in HCC patients’ sera tested compared with control subjects. The reduction occurs with a concomitant increase in the expression of miR-661. Furthermore, the introduction of exogenous hsa-circ-0000221 into Hep-G2 or SNU449 cell lines results in detectable decrease in cellular viability and an increase in apoptotic manifestations that is associated with G1 accumulation and CCDN1 overexpression. Altogether, these findings indicate the tumor-suppressive role of hsa-circ-0000221 in HCC, which acts through miR-661 inhibition, along with a subsequent PTPN11 mRNA increase, where PTPN11 is known to inhibit cell proliferation in many forms of cancer. Our study encourages further investigation of the role of circRNAs in cancer and their potential use as molecular biomarkers.

Highlights

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the major causes of cancer-related death worldwide [1])
To investigate the role of the circRNA–miRNA–messenger RNAs (mRNAs) regulatory axis in HCC, we performed an in silico networking analysis
We first searched for circRNA-associated competing endogenous RNA relevant to HCC according to previous microarray studies

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the major causes of cancer-related death worldwide [1]). Diagnosis of HCC is possible, and radical surgeries are a common treatment modality with mostly favorable prognostic outcomes [2]. Many patients with HCC are missed with the current diagnostic standards and, lose the operation opportunity. Pharmaceutics 2022, 14, 138 outcome and prognosis of HCC patients, it is imperative to search for more efficient biomarkers to increase the early diagnosis rate of HCC. Many HCC patients respond poorly to sorafenib (the first-line chemotherapeutic therapy for advanced HCC) and develop drug resistance after several months of treatment. Chemotherapeutic resistance in HCC involves different mechanisms, e.g., epithelial–mesenchymal transition, cancer stem cells, autophagy, and epigenetic regulation [3]. Several signaling pathways are enrolled in chemotherapeutic resistance in HCC such as TNFα/NF-κB, Wnt/β-catenin, TGFβ, Ras/MEK/ERK, and JAK/STAT pathways [4]

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Conclusion