Special Issue "Cellular and Molecular Mechanisms of Hepatocellular Carcinoma"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 10 March 2020.

Special Issue Editors

Prof. Dr. Sung-Hoon Kim
E-Mail Website
Guest Editor
Department of Oriental Pathology, College of Oriental Medicine, Kyunghee University, Seoul, Korea
Interests: development of chemopreventive cancer agents (metastasis and angiogenesis inhibitors) and functional food (pharmaceuticals); isolation of effective compounds for the prevention or treatment of kidney stones from medicinal herbs
Special Issues and Collections in MDPI journals
Prof. Dr. Sanjay K. Srivastava
E-Mail Website
Guest Editor
1. Distinguished Professor and Chairman, Department of Immunotherapeutics and Biotechnology, Suite 1305, 1718 Pine Street, Abilene, TX 79601, USA
2. Associate Dean for Sciences, Suite 2101 ARB, Texas Tech University Health Sciences Center, 1406 Coulter Drive, Amarillo, TX 79106, USA
Interests: development of phytochemicals for cancer prevention and therapeutics; targeting STAT-3, NF-kB, HER2, MCL-1, AKT/FOXO, GLI1/2, and related signaling pathways with agents such as capsaicin, piperlongumine, penfluridol, isothiocyanates, diindolylmethane, panabinostat, cucurbitacin B, and deguelin in pancreatic, ovarian, breast, melanoma, and brain cancer; drug repurposing
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Liver cancer is known as the second most common cause of cancer-related death worldwide, with a steadily increasing rate of incidence and mortality. Liver cancer usually comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), fibrolamellar HCC (FLC), and the pediatric neoplasm hepatoblastoma.

It is well documented that mature hepatocytes can dedifferentiate into nestin-positive progenitor-like cells to generate primary liver cancers, and chronic inflammation contributes to liver carcinogenesis through cell survival and proliferation signals that promote the formation of regenerative nodules, dysplasia, and cancer via the activation of tumor necrosis factor, interleukin (IL)-6, FOXO, JAK–STAT, nuclear factor κB, insulin-like growth factor, and mTOR or stem cell markers, hedgehog, NOTCH, VEGF, and noncoding RNAs, including miRNAs, siRNAs, PIWI-interacting RNAs (piRNAs ), and long coding RNAs.

The main focus of this Special Issue will be to evaluate cellular and molecular mechanisms and the potential of synthetic or natural compounds for the treatment of liver cancers. Thus, this Special Issue will provide a platform for all pharmaceutical and translational scientists to learn important breakthroughs in drug discovery and new therapeutics in this field.

Potential topics include, but are not limited to, the following:

  1. Molecular mechanisms related to hepatocellular progression:
    1. Epithelial to mesenchymal transition (EMT);
    2. VEGF antagonists and VEGFR inhibitors;
    3. Antagonists of integrins (avb3, avb5, a5b1, etc.).
  2. Metabolic alterations in hepatocellular progression:
    1. Obesity and mesenchymal stem cells;
    2. Lipid synthesis and metabolism: i.e., fatty acid synthase (FASN) and AMACR;
    3. Stroma–cancer cell interactions and hypoxia;
    4. Fatty liver pathogenesis.
  3. Cellular alterations in liver diseases, including liver fibrosis and cancer:
    1. Regulation of ECM components in fibrotic liver;
    2. Modulation of myofibroblasts in liver fibrosis;
    3. Inactivation of hepatic stellate cells for liver cancer treatment.
  4. Strategy to overcome resistance to radiotherapy or chemotherapy:
    1. Tyrosin kinase inhibitor resistance;
    2. Radio-sensitizing;
    3. Antagonists of cell recruitment (monocytes, granulocytes, cancer stem cell-like cells).
  5. Inflammation-associated signaling in liver cancer: mechanisms and clinical implications.
  6. Chemopreventive agents for liver cancer treatment:
    1. Synthetic compounds;
    2. Phytochemicals.

Prof. Sung-Hoon Kim
Prof. Sanjay K. Srivastava
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


  • hepatocellular carcinoma
  • liver fibrosis
  • molecular mechanism
  • cellular alterations
  • inflammation
  • chemoprevention

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Published Papers (1 paper)

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Open AccessArticle
Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation
Cells 2019, 8(11), 1466; https://doi.org/10.3390/cells8111466 - 19 Nov 2019
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown strong and explicit cancer cell-selectivity, which results in little toxicity toward normal tissues, and has been recognized as a potential, relatively safe anticancer agent. However, several cancers are resistant to the apoptosis induced by [...] Read more.
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown strong and explicit cancer cell-selectivity, which results in little toxicity toward normal tissues, and has been recognized as a potential, relatively safe anticancer agent. However, several cancers are resistant to the apoptosis induced by TRAIL. A recent study found that shikonin b (alkannin, 5,8-dihydroxy-2-[(1S)-1-hydroxy-4-methylpent-3-en-1-yl]naphthalene-1,4-dione) might induce apoptosis in TRAIL-resistant cholangiocarcinoma cells through reactive oxygen species (ROS)-mediated caspases activation. However, the strong cytotoxic activity has limited its potential as an anticancer drug. Thus, the current study intends to discover novel shikonin derivatives which can sensitize the liver cancer cell to TRAIL-induced apoptosis while exhibiting little toxicity toward the normal hepatic cell. The trypan blue exclusion assay, western blot assay, 4′,6-diamidino-2-phenylindole (DAPI) staining and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay as well as the ‘comet’ assay, were used to study the underlying mechanisms of cell death and to search for any mechanisms of an enhancement of TRAIL-mediated apoptosis in the presence of ASH. Herein, we demonstrated that non-cytotoxic doses of acetylshikonin (ASH), one of the shikonin derivatives, in combination with TRAIL, could promote apoptosis in HepG2 cells. Further studies showed that application of ASH in a non-cytotoxic dose (2.5 μM) could increase intracellular ROS production and induce DNA damage, which might trigger a cell intrinsic apoptosis pathway in the TRAIL-resistant HepG2 cell. Combination treatment with a non-cytotoxic dose of ASH and TRAIL activated caspase and increased the cleavage of PARP-1 in the HepG2 cell. However, when intracellular ROS production was suppressed by N-acetyl-l-cysteine (NAC), the synergistic effects of ASH and TRAIL on hepatocellular carcinoma (HCC) cell apoptosis was abolished. Furthermore, NAC could alleviate p53 and the p53 upregulated modulator of apoptosis (PUMA) expression induced by TRAIL and ASH. Small (or short) interfering RNA (siRNA) targeting PUMA or p53 significantly reversed ASH-mediated sensitization to TRAIL-induced apoptosis. In addition, Bax gene deficiency also abolished ASH-induced TRAIL sensitization. An orthotopical HCC implantation mice model further confirmed that co-treated ASH overcomes TRAIL resistance in HCC cells without exhibiting potent toxicity in vivo. In conclusion, the above data suggested that ROS could induce DNA damage and activating p53/PUMA/Bax signaling, and thus, this resulted in the permeabilization of mitochondrial outer membrane and activating caspases as well as sensitizing the HCC cell to apoptosis induced by TRAIL and ASH treatment. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Hepatocellular Carcinoma)
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