Mutant MYO1F Alters the Mitochondrial Network and Induces Tumor Proliferation in Thyroid Cancer

Int J Cancer. 2018 Oct 1;143(7):1706-1719. doi: 10.1002/ijc.31548. Epub 2018 May 7.

Abstract

Familial aggregation is a significant risk factor for the development of thyroid cancer and familial non-medullary thyroid cancer (FNMTC) accounts for 5-7% of all NMTC. Whole exome sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a novel heterozygous mutation (c.400G > A, NM_012335; p.Gly134Ser) in exon 5 of MYO1F, mapping to the linkage locus. In the thyroid FRTL-5 cell model stably expressing the mutant MYO1F p.Gly134Ser protein, we observed an altered mitochondrial network, with increased mitochondrial mass and a significant increase in both intracellular and extracellular reactive oxygen species, compared to cells expressing the wild-type (wt) protein or carrying the empty vector. The mutation conferred a significant advantage in colony formation, invasion and anchorage-independent growth. These data were corroborated by in vivo studies in zebrafish, since we demonstrated that the mutant MYO1F p.Gly134Ser, when overexpressed, can induce proliferation in whole vertebrate embryos, compared to the wt one. MYO1F screening in additional 192 FNMTC families identified another variant in exon 7, which leads to exon skipping, and is predicted to alter the ATP-binding domain in MYO1F. Our study identified for the first time a role for MYO1F in NMTC.

Keywords: MYO1F; TCO locus; mitochondrial network; non-medullary thyroid carcinoma; whole exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Cell Proliferation*
  • Cells, Cultured
  • Child
  • Chromosomes, Human, Pair 19
  • Embryo, Nonmammalian / metabolism
  • Embryo, Nonmammalian / pathology*
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mutation*
  • Myosin Type I / chemistry
  • Myosin Type I / genetics*
  • Myosin Type I / metabolism
  • Oxygen Consumption
  • Pedigree
  • Protein Conformation
  • Thyroid Cancer, Papillary / genetics
  • Thyroid Cancer, Papillary / metabolism
  • Thyroid Cancer, Papillary / pathology*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology*
  • Young Adult
  • Zebrafish

Substances

  • MYO1F protein, human
  • Myosin Type I