Investigating MIRNA-661 and
            <i>ATG4-B</i>
            MRNA Expression as Potential Biomarkers for Hepatocellular Carcinoma

Ali, Mahmoud; Matboli, Marwa; El-Khazragy⃰, Nashwa; Saber, Osama; El‐Nakeep, Sarah; Abdelzaher, Hana; Shafei, Ayman; Mostafa, Randa

doi:10.2217/bmm-2017-0273

Cited by 11 publications

(9 citation statements)

References 36 publications

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“…Among those, more than 60% (14/23) of the genes showed an independent impact on overall survival in the TCGA-LIHC cohort as revealed by multivariate analyses ( Figure 5D and Supplemental Tables 11 and 12 ). Importantly, only a few genes were previously implicated with liver cancer development (ATG4B, CCR5, MCM6, and UCN ) ( 26 – 29 ), whereas most of the epidrivers were newly identified.…”

Section: Discussionmentioning

confidence: 99%

“…Signaling pathway analyses of the putative epi-drivers further centered on molecular mechanisms of cancer, cell survival, proliferation and invasion as well as stem cell activation and immune regulation (Supplemental Figure 5B). While some genes (ATG4B, CCR5, MCM6, UCN) were detected in the context hepatocarcinogenesis before, most of the epi-drivers were result of the investigation of our unique cohort (26)(27)(28)(29).…”

Section: Identification and Validation Of Epi-drivers In Hcc Development And Progressionmentioning

confidence: 99%

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Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis

et al. 2021

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Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver ( n = 7), low- ( n = 4) and high-grade ( n = 9) dysplastic lesions, and early ( n = 5) and progressed ( n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further employed for clonality analyses, indicating multiclonal origin in the majority of investigated HCCs. Alterations in DNA methylation progressively increased from liver cirrhosis (CL) to dysplastic lesions and reached a maximum in early HCCs. Associated early alterations identified by Ingenuity Pathway Analysis (IPA) involved apoptosis, immune regulation, and stemness pathways, while late changes centered on cell survival, proliferation, and invasion. We further validated 23 putative epidrivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated, and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines. Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for potentially novel therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Identification and Validation Of Epi-drivers In Hcc Development And Progressionmentioning

confidence: 99%

Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis

et al. 2021

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“…At present, there are only few studies of this miRNA and its relationship to cancer. A study by Ali et al revealed that the combined analysis of hsa-miR-661-3p and ATG-4B gene content could be a marker for clinical diagnosis and prognosis of liver cancer (31). In addition, it has been reported that hsa-miR-661-3p played an important role in the maintenance of redox and metabolic balance of intestinal cancer cells (32).…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of hsa‑miR661‑3p on non‑small cell lung cancer in vivo and in vitro

Liu

et al. 2019

Oncol Rep

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Lung cancer is the most common and lethal cancer worldwide, especially in developing countries. Non-small cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer. In aprevious study, the protein expression of ubiquitin conjugating enzyme E2 C (UBE2C/UbcH10) in NSCLC tissues and cells was found to be significantly higher than that in adjacent tissues and normal lung epithelial cells. Further study revealed that the aberrant expression of UbcH10 in NSCLC tumors or cancer cells was caused by inactivation of the post-transcriptional regulation mechanism, and thus microRNAs (miRNAs) may play an important. In the present study, it was demonstrated that the expression of microRNA, hsa-miR661-3p, was downregulated and UbcH10 was upregulated in 12 pairs of NSCLC tumors and three NSCLC cell lines. A reporter gene assay revealed that overexpression of hsa-miR661-3p effectively reduced the activity of luciferase expressed by a vector bearing the 3' untranslated region of UbcH10 mRNA. Ectopic hsa-miR661-3p overexpression mediated by lentiviral infection decreased the expression of UbcH10. Infection of Lv-miR661-3p inhibited cell growth and invasion in A549 and SK-MES-1 cells. Mechanistically, hsa-miR661-3p induced cell cycle G2 arrest through regulation of spindle assembly checkpoint (SAC) function. On the basis of the proposed mechanisms, the objective of the study was to inhibit the proliferation of A549 and SK-MES-1 by expressing hsa-miR661-3p in vivo and in vitro. Collectively, our results indicated that downregulation of hsa-miR661-3p was involved in NSCLC and restoration of hsa-miR661-3p impaired the growth of NSCLC cell lines A549 and SK-MES-1, suggesting that hsa-miR661-3p may be a potential target molecule for the therapy of NSCLC.

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“…MiR‐34a, miR‐34c, miR‐449a, miR‐449‐5p, and miR‐665‐3p can target ATG4B, affecting autophagy in various pathological processes 42–50 . Additionally, miR‐16, miR24‐2, miR‐34c‐5p, and miR‐661 increase the protein levels of ATG4B to activate cytoprotective autophagy in the development of diverse tumors 51–54 . MiR‐129‐3p enhances intracellular BCG survival by repressing autophagy via ATG4B 55 .…”

Section: The Regulatory Factors Of Atg4mentioning

confidence: 99%

“…For example, Luo et al reported that BOLA2 is closely associated with both the activation of p62‐Keap1 signaling and ATG4B expression according to Gene Expression Profiling Interactive Analysis in a training cohort of HCC samples 125 . Likewise, the expression levels of miR‐661 and ATG4B through bioinformatics‐based selection were higher in the HCC serum group than in the healthy control group 54 . Additionally, heat shock transcription factor 1 (HSF1) and early growth response factor (Egr‐1) elevate ATG4B levels by promoting its transcription through binding to the ATG4B gene promotor region.…”

Section: Atg4 and Diseasesmentioning

confidence: 99%

The regulatory factors and pathological roles of autophagy‐related protein 4 in diverse diseases: Recent research advances

Xia

Liu

2020

Medicinal Research Reviews

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Macroautophagy (autophagy) is an evolutionarily conserved and dynamic degradation/recycling pathway in which portions of the cytoplasm, such as dysfunctional proteins and surplus organelles, are engulfed by double‐membrane bound vesicles through a lysosome‐dependent process. As the only proteolytic enzyme of the core mammalian autophagy proteins, autophagy‐related protein 4 (ATG4) primes newly synthesized pro‐light chain 3 (LC3) to form LC3‐I that attaches to phosphatidylethanolamine and delipidates LC3‐PE to LC3‐I for recycling. Besides autophagy, ATG4 has been shown to be involved in regulating various biological and pathological processes. The roles of ATG4 in cancer therapy, a methodology for ATG4 activity detection, and the discovery of chemical modulators have been well‐reviewed. However, a comprehensive summary on how ATG4 is regulated by multiple factors and, thereby, how ATG4 influences autophagy or other pathways remains lacking. In this paper, we summarize multiple processes and molecules that regulate the activity of ATG4, such as micro‐RNAs, posttranslational modifications, and small molecules. Additionally, we focus on the relationship between ATG4 and diverse diseases, including cancer, neurodegeneration, microbial infection, and other diseases. It provides insight regarding potential ATG4‐targeted therapeutic opportunities, which could be beneficial for future studies and human health.

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Investigating MIRNA-661 and ATG4-B MRNA Expression as Potential Biomarkers for Hepatocellular Carcinoma

Abstract: Our data are the first report of its kind regarding the considerable clinical significance of miR-661 and ATG-4B mRNA in HCC patients.

Cited by 11 publications

References 36 publications

Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis

Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis

Antitumor effects of hsa‑miR661‑3p on non‑small cell lung cancer in vivo and in vitro

The regulatory factors and pathological roles of autophagy‐related protein 4 in diverse diseases: Recent research advances

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