ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma

Arechederra, María; Bazai, Sehrish K.; Abdouni, Ahmed; Sequera, Celia; Mead, Timothy J.; Richelme, Sylvie; Daian, Fabrice; Audebert, Stéphane; Dono, Rosanna; Lozano, Anthony; Grégoire, Damien; Hibner, Urszula; Allende, Daniela S.; Apte, Suneel S.; Maina, Flavio

doi:10.1016/j.jhep.2020.11.008

Cited by 44 publications

(38 citation statements)

References 34 publications

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“…Previous research has shown that targeting ADAMTSL5 in hepatocellular carcinoma cells interfered with tumorigenic properties, and that ADAMTSL5 acts upstream of several key oncogenic pathways, such as EGFR, MET, PDGFRβ, IGF1Rβ, and FGFR4. This phenotype confers sensitivity to several targeted drugs, including lenvatinib, sorafenib, and regorafenib (16). Together with the present results, we speculated that ADAMTSL family members were multifunctional and that the secreted ADAMTSLs act in a non-cell autonomous fashion, and as potential master regulators inside cells.…”

Section: Discussionsupporting

confidence: 80%

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The potential prognostic values of the ADAMTS-like protein family: an integrative pan-cancer analysis

et al. 2021

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Section: Discussionsupporting

confidence: 80%

“…ADAMTSL2 mutations led to geleophysic dysplasia, including stiff skin and cardiac anomalies (15). ADAMTSL3 and ADAMTSL5 suppress hepatocellular carcinoma proliferation and metastasis (16,17). In particular, ADAMTSL4 was localized to the lens equator and anchored microfibrils into the lens capsule (18).…”

Section: Introductionmentioning

confidence: 99%

The potential prognostic values of the ADAMTS-like protein family: an integrative pan-cancer analysis

et al. 2021

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“…The relative content of macrophages under the TIMER database was elevated in the high-risk group. It is known that drug therapy is crucial for the treatment of HCC [ 44 , 45 ]. Previous studies have identified Doxorubicin as an effective drug to inhibit HCC via the regulation of apoptosis [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Signature Construction and Molecular Subtype Identification Based on Pyroptosis-Related Genes for Better Prediction of Prognosis in Hepatocellular Carcinoma

Chen

Tao

Lang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there is a lack of adequate means of treatment prognostication for HCC. Pyroptosis is a newly discovered way of programmed cell death. However, the prognostic role of pyroptosis in HCC has not been thoroughly investigated. Here, we generated a novel prognostic signature to evaluate the prognostic value of pyroptosis-related genes (PRGs) using the data from The Cancer Genome Atlas (TCGA) database. The accuracy of the signature was validated using survival analysis through the International Cancer Genome Consortium cohort ( n = 231 ) and the First Affiliated Hospital of Wenzhou Medical University cohort ( n = 180 ). Compared with other clinical factors, the risk score of the signature was found to be associated with better patient outcomes. The enrichment analysis identified multiple pathways related with pyroptosis in HCC. Furthermore, drug sensitivity testing identified six potential chemotherapeutic agents to provide possible treatment avenues. Interestingly, patients with low risk were confirmed to be associated with lower tumor mutation burden (TMB). However, patients at high risk were found to have a higher count of immune cells. Consensus clustering was performed to identify two main molecular subtypes (named clusters A and B) based on the signature. It was found that compared with cluster B, better survival outcomes and lower TMB were observed in cluster A. In conclusion, signature construction and molecular subtype identification of PRGs could be used to predict the prognosis of HCC, which may provide a specific reference for the development of novel biomarkers for HCC treatment.

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“…Upregulation of Axl was associated with augmented levels of SHP2 in sorafenib-resistant HCC cells. Conversely, recent findings of cellular HCC models proposed that upon knockdown of ADAMTSL5, a potent mediator of oncogenic signaling and chemoresistance, Axl expression is increased [52]. Currently, a functional implication of Axl in HCC patients resistant to TKIs, such as sorafenib, remains to be elucidated [51].…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, augmented levels of Src homology domain-containing phosphatase 2 (SHP2) in sorafenib-resistant HCC cells correlate with RTK activation, including Axl [51]. On the contrary, a recent study revealed the upregulation of Axl after abrogation of ADAMTSL5, a crucial regulator of oncogenic signaling and chemoresistance in HCC, suggesting a role in the acquisition of chemosensitivity rather than in its escape from drug treatment [52].…”

Section: Tam Receptors In Liver Pathophysiologymentioning

confidence: 99%

Intrinsic and Extrinsic Control of Hepatocellular Carcinoma by TAM Receptors

Hedrich

Breitenecker

Djerlek

et al. 2021

Cancers

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Hepatocellular carcinoma (HCC) is the major subtype of liver cancer, showing high mortality of patients due to limited therapeutic options at advanced stages of disease. The receptor tyrosine kinases Tyro3, Axl and MerTK—belonging to the TAM family—exert a large impact on various aspects of cancer biology. Binding of the ligands Gas6 or Protein S activates TAM receptors causing homophilic dimerization and heterophilic interactions with other receptors to modulate effector functions. In this context, TAM receptors are major regulators of anti-inflammatory responses and vessel integrity, including platelet aggregation as well as resistance to chemotherapy. In this review, we discuss the relevance of TAM receptors in the intrinsic control of HCC progression by modulating epithelial cell plasticity and by promoting metastatic traits of neoplastic hepatocytes. Depending on different etiologies of HCC, we further describe the overt role of TAM receptors in the extrinsic control of HCC progression by focusing on immune cell infiltration and fibrogenesis. Additionally, we assess TAM receptor functions in the chemoresistance against clinically used tyrosine kinase inhibitors and immune checkpoint blockade in HCC progression. We finally address the question of whether inhibition of TAM receptors can be envisaged for novel therapeutic strategies in HCC.

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ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma

Cited by 44 publications

References 34 publications

The potential prognostic values of the ADAMTS-like protein family: an integrative pan-cancer analysis

The potential prognostic values of the ADAMTS-like protein family: an integrative pan-cancer analysis

Signature Construction and Molecular Subtype Identification Based on Pyroptosis-Related Genes for Better Prediction of Prognosis in Hepatocellular Carcinoma

Intrinsic and Extrinsic Control of Hepatocellular Carcinoma by TAM Receptors

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