Targeting of MIR-518D Reduces Chemoresistance in Hepatocellular Carcinoma Cell Lines

Ramos, Débora Felicia Vieira; Tussy, Pablo Fernández; Banales, J.M.; Briz, Óscar; Herráez, Elisa; Marin, J.J.G.; Mato, José M.; Chantar, M.L.M.

doi:10.1016/s0168-8278(16)01014-x

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“…1 A). BCLC-3 WT cells exhibited higher resistance to sorafenib, which is in line with previously published studies [ 43 , 44 ]. In the next set of experiments, additional parameters of 3D spheroid cultures including morphology and solidity were monitored (Suppl.…”

Section: Resultssupporting

confidence: 92%

Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells

Rodrigo,

Michalkova,

Jimenez

et al. 2024

Biomark Res

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Background & aims Metallothionein-3 (hMT3) is a structurally unique member of the metallothioneins family of low-mass cysteine-rich proteins. hMT3 has poorly characterized functions, and its importance for hepatocellular carcinoma (HCC) cells has not yet been elucidated. Therefore, we investigated the molecular mechanisms driven by hMT3 with a special emphasis on susceptibility to sorafenib. Methods Intrinsically sorafenib-resistant (BCLC-3) and sensitive (Huh7) cells with or without up-regulated hMT3 were examined using cDNA microarray and methods aimed at mitochondrial flux, oxidative status, cell death, and cell cycle. In addition, in ovo/ex ovo chick chorioallantoic membrane (CAM) assays were conducted to determine a role of hMT3 in resistance to sorafenib and associated cancer hallmarks, such as angiogenesis and metastastic spread. Molecular aspects of hMT3-mediated induction of sorafenib-resistant phenotype were delineated using mass-spectrometry-based proteomics. Results The phenotype of sensitive HCC cells can be remodeled into sorafenib-resistant one via up-regulation of hMT3. hMT3 has a profound effect on mitochondrial respiration, glycolysis, and redox homeostasis. Proteomic analyses revealed a number of hMT3-affected biological pathways, including exocytosis, glycolysis, apoptosis, angiogenesis, and cellular stress, which drive resistance to sorafenib. Conclusions hMT3 acts as a multifunctional driver capable of inducing sorafenib-resistant phenotype of HCC cells. Our data suggest that hMT3 and related pathways could serve as possible druggable targets to improve therapeutic outcomes in patients with sorafenib-resistant HCC.

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Section: Resultssupporting

confidence: 92%