Hepatocellular carcinoma treatment over sorafenib: epigenetics, microRNAs and microenvironment. Is there a light at the end of the tunnel?

Gaspar, António; Santini, Daniele; Scartozzi, Mario; Russo, Antonio; Licchetta, Antonella; Palmieri, Vincenzo O.; Lupo, L.; Faloppi, Luca; Palasciano, Giuseppe; Memeo, V.; Angarano, Gioacchino; Brunetti, Oronzo; Giacosa, Attilio; Pisconti, Salvatore; Lorusso, Vito; Silvestris, Nicola

doi:10.1517/14728222.2015.1071354

Cited by 61 publications

(44 citation statements)

References 111 publications

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“…Molecular analysis, based on testing a small piece of tumor, might underestimate the complexity of tumor genomics. Therefore, exploring the molecular pathways involved in hepatocarcinogenesis might provide new therapeutic targets in HCC and molecular-based individualized therapies, not underestimating the tumor microenvironment and its roles in angiogenesis or immune system [36].…”

Section: Reg3a Is a Key Molecule Modulated By Crosstalk Between Hcc Cmentioning

confidence: 99%

Tumor-Stroma Crosstalk Enhances REG3A Expressions that Drive the Progression of Hepatocellular Carcinoma

Cho

Park

Kim

et al. 2020

IJMS

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Background: Crosstalk between tumors and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). However, there is little existing information about the key signaling molecule that modulates tumor-stroma crosstalk. Methods: Complementary DNA (cDNA) microarray analysis was performed to identify the key molecule in tumor-stroma crosstalk. Subcutaneous xenograft in vivo murine model, immunoblotting, immunofluorescence, and real-time polymerase chain reaction using HCC cells and tissues were performed. Results: The key molecule, regenerating gene protein-3A (REG3A), was most significantly enhanced when coculturing HCC cells and activated human hepatic stellate cells (HSCs) (+8.2 log) compared with monoculturing HCC cells using cDNA microarray analysis. Downregulation of REG3A using small interfering RNA significantly decreased the proliferation of HSC-cocultured HCC cells in vitro and in vivo, and enhanced deoxycholic acid-induced HCC cell apoptosis. Crosstalk-induced REG3A upregulation was modulated by platelet-derived growth factor ββ (PDGF-ββ) in p42/44-dependent manner. REG3A mRNA levels in human HCC tissues were upregulated 1.8-fold compared with non-tumor tissues and positively correlated with PDGF-ββ levels. Conclusions: REG3A/p42/44 pathway/PDGF-ββ signaling plays a significant role in hepatocarcinogenesis via tumor-stroma crosstalk. Targeting REG3A is a potential novel therapeutic target for the management of HCCs by inhibiting crosstalk between HCC cells and HSCs.

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Section: Reg3a Is a Key Molecule Modulated By Crosstalk Between Hcc Cmentioning

confidence: 99%

Tumor-Stroma Crosstalk Enhances REG3A Expressions that Drive the Progression of Hepatocellular Carcinoma

Cho

Park

Kim

et al. 2020

IJMS

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“…70 Further studies are still ongoing to determine its safety and efficacy. 71 Additionally, carrageenan has been formulated as a prophylactic microbicidal gel to block HIV and HPV infection. 72 Unfortunately, it failed in a Phase III trial and has been discontinued.…”

Section: Targeting Heparan Sulfate-protein Interactionsmentioning

confidence: 99%

Targeting heparin and heparan sulfate protein interactions

2017

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Heparin and heparan sulfate glycosaminoglycans are long, linear polysaccharides that are made up of alternating dissacharide sequences of highly sulfated uronic acid and amino sugars. Unlike heparin, which is only found in mast cells, heparan sulfate is ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These negatively-charged carbohydrate chains play essential roles in important cellular functions such as cell growth, adhesion, angiogenesis, and blood coagulation. However, these biomolecules are also involved in pathophysiological conditions such as pathogen infection and human disease. This review discusses past and current methods for targeting these complex biomolecules as a novel therapeutic strategy to treating disorders such as cancer, neurodegenerative diseases, and infection.

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“…Primary liver cancer types include hepatocellular carcinoma and cholangiocarcinoma; the most frequent original sites of metastasis in liver cancer are the stomach, pancreas and colon (1). Surgery is the most effective curative treatment for primary and metastatic liver cancer (2,3); however, if surgery is not a viable option, chemotherapy or molecular target therapy are considered for further treatment (4)(5)(6). The agents used in chemotherapy and molecular targeted therapy frequently cause hepatotoxicity, which limits the efficacy of this treatment (7,8).…”

Section: Introductionmentioning

confidence: 99%

Proliferation and motility of hepatocellular, pancreatic and gastric cancer cells grown in a medium without glucose and arginine, but with galactose and ornithine

et al. 2017

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Abstract. Human primary hepatocytes are able to survive in a medium without glucose and arginine, but supplemented with galactose and ornithine (hepatocyte selection medium; HSM). To address the possibility of the application of HSM in cancer therapy, hepatocellular carcinoma cells, pancreatic cancer cells and gastric cancer cells were cultured in HSM. Cell proliferation was analyzed using an MTS assay. Morphological changes were analyzed using hematoxylin and eosin staining. Apoptosis was analyzed using a TUNEL assay and cell motility was assessed with a scratch assay. Cell proliferation was significantly suppressed in cell lines grown in HSM (P<0.01 in all the cell lines). Hematoxylin and eosin staining revealed pyknotic nuclei, suggesting that these cells had undergone apoptosis. The number of TUNEL-positive cells was significantly increased in HSM. In the scratch assay, the distance between the growing edge and the scratched edge was significantly lower (P<0.01 in all the cell lines) in cells cultured in HSM, compared with those grown in Dulbecco's modified Eagle's medium or RPMI-1640. Therefore, the proliferation and motility of hepatocellular carcinoma cells, pancreatic cancer cells and gastric cancer cells was suppressed, and these cells subsequently underwent apoptosis in a medium without glucose and arginine, but containing galactose and ornithine.

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Hepatocellular carcinoma treatment over sorafenib: epigenetics, microRNAs and microenvironment. Is there a light at the end of the tunnel?

Cited by 61 publications

References 111 publications

Tumor-Stroma Crosstalk Enhances REG3A Expressions that Drive the Progression of Hepatocellular Carcinoma

Tumor-Stroma Crosstalk Enhances REG3A Expressions that Drive the Progression of Hepatocellular Carcinoma

Targeting heparin and heparan sulfate protein interactions

Proliferation and motility of hepatocellular, pancreatic and gastric cancer cells grown in a medium without glucose and arginine, but with galactose and ornithine

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