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. 2022 Jul 22:12:914032.
doi: 10.3389/fonc.2022.914032. eCollection 2022.

A Network-Guided Approach to Discover Phytochemical-Based Anticancer Therapy: Targeting MARK4 for Hepatocellular Carcinoma

Sarfraz Ahmed  1   2 , Mohammad Mobashir  1 , Lamya Ahmed Al-Keridis  3 , Nawaf Alshammari  4 , Mohd Adnan  4 , Mohammad Abid  1 , Md Imtaiyaz Hassan  2
Affiliations

A Network-Guided Approach to Discover Phytochemical-Based Anticancer Therapy: Targeting MARK4 for Hepatocellular Carcinoma

Sarfraz Ahmed et al. Front Oncol. .

Abstract

MAP/microtubule affinity-regulating kinase 4 (MARK4) is associated with various biological functions, including neuronal migration, cell polarity, microtubule dynamics, apoptosis, and cell cycle regulation, specifically in the G1/S checkpoint, cell signaling, and differentiation. It plays a critical role in different types of cancers. Hepatocellular carcinoma (HCC) is the one of the most common forms of liver cancer caused due to mutations, epigenetic aberrations, and altered gene expression patterns. Here, we have applied an integrated network biology approach to see the potential links of MARK4 in HCC, and subsequently identified potential herbal drugs. This work focuses on the naturally-derived compounds from medicinal plants and their properties, making them targets for potential anti-hepatocellular treatments. We further analyzed the HCC mutated genes from the TCGA database by using cBioPortal and mapped out the MARK4 targets among the mutated list. MARK4 and Mimosin, Quercetin, and Resveratrol could potentially interact with critical cancer-associated proteins. A set of the hepatocellular carcinoma altered genes is directly the part of infection, inflammation, immune systems, and cancer pathways. Finally, we conclude that among all these drugs, Gingerol and Fisetin appear to be the highly promising drugs against MARK4-based targets, followed by Quercetin, Resveratrol, and Apigenin.

Keywords: HCC; MARK4; biological networks; clinical relevance; herbal drugs; potential genes; signaling pathways.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
MARK4-interactors profiling and potential drugs target properties. (A) Workflow of this study. (B) Top-ranked MARK4 interactors. (C) MARK4-associated pathways.
Figure 2
Figure 2
(A) Selected herbal drugs and their potential proteins interact with the respective drugs. Here, the pie chart represents the classes of the proteins. (B) Vanillin-associated proteins.
Figure 3
Figure 3
Networks for the selected herbal drugs and their potential proteins interacting with the respective drugs (A-F).
Figure 4
Figure 4
Proteins are common with the selected herbal drug target proteins interacting.
Figure 5
Figure 5
Mutational profiling and pathway-level understanding. (A) Top-ranked genes based on a mutation in the selected dataset for overall genes in the case of HCC and the genes common to MARK4-interactors. (B) Network representing top-ranked mutated genes associated with MARK4. (C) Venn diagram to map out the common and exclusively enriched pathways.
Figure 6
Figure 6
Functional impact of mutation in case of HCC. (A) Overall enriched pathways with their respective p-values in the case of HCC. (B, C) represents those mutated genes and belongs to the TCGA PanCancer Atlas pathways acting as major role players.
Figure 7
Figure 7
Clinical relevance. (A) Overall highly mutated genes in the case of HCC. (B) Percentage of patients showing a mutation in MARK4 and (C) survival curve representing the significance of MARK4 in the HCC clinical samples.
See this image and copyright information in PMC

References

    1. Cui Q, Ma Y, Jaramillo M, Bari H, Awan A, Yang S, et al. A Map of Human Cancer Signaling. Mol Syst Biol (2007) 3:1–13. doi: 10.1038/msb4100200 - DOI - PMC - PubMed
    1. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell (2011) 144:646–74. doi: 10.1016/j.cell.2011.02.013 - DOI - PubMed
    1. Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J. Cancer: A Systems Biology Disease. Biosystems (2006) 83:81–90. doi: 10.1016/j.biosystems.2005.05.014 - DOI - PubMed
    1. Saraste A, Pulkki K. Morphologic and Biochemical Hallmarks of Apoptosis. Cardiovasc Res (2000) 45:528–37. doi: 10.1016/S0008-6363(99)00384-3 - DOI - PubMed
    1. Consortium, T. I. C. G. committee, E. committee, E. A. P. group, T. A. C. A. W. group, T. W. group, B. A. W et al. PERSPECTIVES. Nature (2010) 464:993–8. doi: 10.1038/nature08987 - DOI

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