Hepatic stellate cells induce hepatocellular carcinoma cell resistance to sorafenib through the laminin‐332/α3 integrin axis recovery of focal adhesion kinase ubiquitination

Azzariti, Amalia; Mancarella, Serena; Porcelli, Letizia; Quatrale, Anna Elisa; Caligiuri, Alessandra; Lupo, L.; Dituri, Francesco; Giannelli, Gianluigi

doi:10.1002/hep.28835

Cited by 89 publications

(79 citation statements)

References 27 publications

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“…In fact, the effects, resulting from FAK-dependent deregulation of EZH2 transcriptional repression of specific targets, may converge to reinforce HCC sensitivity to selective FAK inhibition possibly reducing both local tumor growth and distant metastasis. Furthermore, since Azzariti et al have recently reported 48 a novel mechanism by which Sorafenib may induce HCC cell resistance through Laminin-332/ α 3 integrin-dependent escape of FAK from ubiquitination and consequent degradation, it is plausible that pharmacological inhibition of FAK may also enhance Sorafenib therapeutic performance. This information provides a proof-of-concept that drugs acting against FAK and EZH2, either those already approved by Food and Drug Administration or new ones, could represent a therapeutic option for HCC.…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2

Gnani

Romito

Artuso³

et al. 2017

Cell Death Differ

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Hepatocellular carcinoma (HCC) is the most common type of liver cancer in humans. The focal adhesion tyrosine kinase (FAK) is often over-expressed in human HCC and FAK inhibition may reduce HCC cell invasiveness. However, the anti-oncogenic effect of FAK knockdown in HCC cells remains to be clarified. We found that FAK depletion in HCC cells reduced in vitro and in vivo tumorigenicity, by inducing G2/M arrest and apoptosis, decreasing anchorage-independent growth, and modulating the expression of several cancer-related genes. Among these genes, we showed that FAK silencing decreased transcription and nuclear localization of enhancer of zeste homolog 2 (EZH2) and its tri-methylation activity on lysine 27 of histone H3 (H3K27me3). Accordingly, FAK, EZH2 and H3K27me3 were concomitantly upregulated in human HCCs compared to non-tumor livers. In vitro experiments demonstrated that FAK affected EZH2 expression and function by modulating, at least in part, p53 and E2F2/3 transcriptional activity. Moreover, FAK silencing downregulated both EZH2 binding and histone H3K27me3 levels at the promoter of its target gene NOTCH2. Finally, we found that pharmacological inhibition of FAK activity resembled these effects although milder. In summary, we demonstrate that FAK depletion reduces HCC cell growth by affecting cancer-promoting genes including the pro-oncogene EZH2. Furthermore, we unveil a novel unprecedented FAK/EZH2 crosstalk in HCC cells, thus identifying a targetable network paving the way for new anticancer therapies.

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Section: Discussionmentioning

confidence: 99%

Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2

Gnani

Romito

Artuso³

et al. 2017

Cell Death Differ

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“…HCC cells secrete cytokines and chemokines to promote the activation of HSCs, while activated HSCs also produce chemokines to promote tumor cell proliferation and migration [21]. A recent study demonstrated that HSCs induce HCC resistance to sorafenib [22]. This indicates the potential involvement of tumor fibrosis in the development of resistance to sorafenib in HCC.…”

Section: Discussionmentioning

confidence: 99%

Synergistic anti-tumor efficacy of sorafenib and fluvastatin in hepatocellular carcinoma

et al. 2017

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Drug resistance to sorafenib is common in patients with hepatocellular carcinoma(HCC). We examined the effects of a combination of sorafenib and fluvastatin on HCC using in vitro and in vivo models. The dual treatment induced apoptosis and reduced cellular viability in HCC more effectively than either drug alone. The combination treatment also inhibited activation of hepatic stellate cells, whereas single drug treatments did not. On a molecular level, combined treatment inhibited activation of the MAPK and NF-κB pathways via Toll-like receptor 4 in HCC cells. Combined treatment also inhibited expression of stromal cell-derived factor 1α in HCC cells, which further inhibited the MAPK pathway in hepatic stellate cells. These results suggest that a combination of sorafenib and fluvastatin may be a promising therapeutic strategy for patients with advanced HCC.

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“…The mutual and symbiotic interconnections between anabolic CRC cells and highly abundant catabolic stromal fibroblasts or cancer- associated fibroblast (CAFs) favor the development of tumors and metastases [7]. Moreover, substantial studies recognize HSCs as the main matrix- producing cells in liver fibrosis [8]. …”

Section: Introductionmentioning

confidence: 99%

Non-coding RNAs, the Trojan horse in two-way communication between tumor and stroma in colorectal and hepatocellular carcinoma

et al. 2017

Self Cite

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In a continuous and mutual exchange of information, cancer cells are invariably exposed to microenvironment transformation. This continuous alteration of the genetic, molecular and cellular peritumoral stroma background has become as critical as the management of primary tumor progression events in cancer cells. The communication between stroma and tumor cells within the extracellular matrix is one of the triggers in colon and liver carcinogenesis. All non- codingRNAs including long non-coding RNAs, microRNAs and ultraconserved genes play a critical role in almost all cancers and are responsible for the modulation of the tumor microenvironment in several malignant processes such as initiation, progression and dissemination. This review details the involvement of non codingRNAs in the evolution of human colorectal carcinoma and hepatocellular carcinoma in relationship with the microenvironment. Recent research has shown that a considerable number of dysregulated non- codingRNAs could be valuable diagnostic and prognostic biomarkers in cancer. Therefore, more in-depth knowledge of the role non- codingRNAs play in stroma-tumor communication and of the complex regulatory mechanisms between ultraconserved genes and microRNAs supports the validation of future effective therapeutic targets in patients suffering from hepatocellular and colorectal carcinoma, two distinctive entities which share quite a lot common non-coding RNAs.

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Hepatic stellate cells induce hepatocellular carcinoma cell resistance to sorafenib through the laminin‐332/α3 integrin axis recovery of focal adhesion kinase ubiquitination

Abstract: This study unveils a novel mechanism of sorafenib resistance depending on the α3β1/Ln-332 axis and requiring FAK ubiquitination, providing new insights into personalizing therapy for patients with HCC. (Hepatology 2016;64:2103-2117).

Cited by 89 publications

References 27 publications

Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2

Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2

Synergistic anti-tumor efficacy of sorafenib and fluvastatin in hepatocellular carcinoma

Non-coding RNAs, the Trojan horse in two-way communication between tumor and stroma in colorectal and hepatocellular carcinoma

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