Splicing factor SF3B1 is overexpressed and implicated in the aggressiveness and survival of hepatocellular carcinoma

Splicing alterations represent an actionable cancer hallmark. Splicing factor 3B subunit 1 (SF3B1) is a crucial splicing factor that can be targeted pharmacologically (e.g. pladienolide-B). Here, we show that SF3B1 is overexpressed (RNA/protein) in hepatocellular carcinoma (HCC) in two retrospective...

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Bibliographic Details
Published in:Cancer letters 2021-01, Vol.496, p.72-83
Main Authors: López-Cánovas, Juan L., del Rio-Moreno, Mercedes, García-Fernandez, Helena, Jiménez-Vacas, Juan M., Moreno-Montilla, M.Trinidad, Sánchez-Frias, Marina E., Amado, Víctor, L-López, Fernando, Fondevila, Marcos F., Ciria, Rubén, Gómez-Luque, Irene, Briceño, Javier, Nogueiras, Rubén, de la Mata, Manuel, Castaño, Justo P., Rodriguez-Perálvarez, Manuel, Luque, Raúl M., Gahete, Manuel D.
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Apoptosis
Bcl-x protein
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Cancer therapies
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Cell migration
Cell Movement
Cell Proliferation
Cell viability
Cyclin-dependent kinase 4
Drug resistance
Female
Gene expression
Gene Expression Regulation, Neoplastic
Hepatocellular carcinoma
Hepatocytes
Humans
KLF6-SV1
Liver cancer
Liver diseases
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Male
Mice
Mice, Nude
Middle Aged
Phosphoproteins - genetics
Phosphoproteins - metabolism
Pladienolide-B
Prognosis
Proteins
Retrospective Studies
Ribonucleic acid
RNA
RNA Splicing Factors - genetics
RNA Splicing Factors - metabolism
Spliceosome
Splicing factors
Survival Rate
Tumor cell lines
Tumor Cells, Cultured
Tumors
Xenograft
Xenograft Model Antitumor Assays
Xenografts
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Summary:Splicing alterations represent an actionable cancer hallmark. Splicing factor 3B subunit 1 (SF3B1) is a crucial splicing factor that can be targeted pharmacologically (e.g. pladienolide-B). Here, we show that SF3B1 is overexpressed (RNA/protein) in hepatocellular carcinoma (HCC) in two retrospective (n = 154 and n = 172 samples) and in five in silico cohorts (n > 900 samples, including TCGA) and that its expression is associated with tumor aggressiveness, oncogenic splicing variants expression (KLF6-SV1, BCL-XL) and decreased overall survival. In vitro, SF3B1 silencing reduced cell viability, proliferation and migration and its pharmacological blockade with pladienolide-B inhibited proliferation, migration, and formation of tumorspheres and colonies in liver cancer cell lines (HepG2, Hep3B, SNU-387), whereas its effects on normal-like hepatocyte-derived THLE-2 proliferation were negligible. Pladienolide-B also reduced the in vivo growth and the expression of tumor-markers in Hep3B-induced xenograft tumors. Moreover, SF3B1 silencing and/or blockade markedly modulated the activation of key signaling pathways (PDK1, GSK3b, ERK, JNK, AMPK) and the expression of cancer-associated genes (CDK4, CD24) and oncogenic SVs (KLF6-SV1). Therefore, the genetic and/or pharmacological inhibition of SF3B1 may represent a promising novel therapeutic strategy worth to be explored through randomized controlled trials. [Display omitted] •The splicing factor SF3B1 is overexpressed in HCC and associated to overall survival.•Genetic silencing of SF3B1 reduces oncogenic potential of HCC cell lines.•SF3B1 pharmacological blockade with pladienolide-B exerts inhibitory effects in HCC.•SF3B1 blockade by pladienolide-B reduces tumor growth in preclinical models.•SF3B1 modulates the expression of key oncogenic splicing variants.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2020.10.010