Combined deletion and DNA methylation result in silencing of FAM107A gene in laryngeal tumors

Abstract

Larynx squamous cell carcinoma (LSCC) is characterized by complex genotypes, with numerous abnormalities in various genes. Despite the progress in diagnosis and treatment of this disease, 5-year survival rates remain unsatisfactory. Therefore, the extended studies are conducted, with the aim to find genes, potentially implicated in this cancer. In this study, we focus on the FAM107A (3p14.3) gene, since we found its significantly reduced expression in LSCC by microarray profiling (Affymetrix U133 Plus 2.0 array). By RT-PCR we have confirmed complete FAM107A downregulation in laryngeal cancer cell lines (15/15) and primary tumors (21/21) and this finding was further supported by FAM107A protein immunohistochemistry (15/15). We further demonstrate that a combined two hit mechanism including loss of 3p and hypermethylation of FAM107A promoter region (in 9/15 cell lines (p < 0.0001) and in 15/21 primary tumors (p < 0.0001)) prevails in the gene transcriptional loss. As a proof of principle, we show that Decitabine - a hypomethylating agent – restores FAM107A expression (5 to 6 fold increase) in the UT-SCC-29 cell line, characterized by high DNA methylation. Therefore, we report the recurrent inactivation of FAM107A in LSCC, what may suggest that the gene is a promising tumor suppressor candidate involved in LSCC development.

Genes and Mechanisms Involved in the Generation and Amplification of Basal Radial Glial Cells

“…67 candidate marker genes were identified that strongly correlated with the human BP/bRG population (Pollen et al, 2014, 2015). Genes were highlighted related to extracellular matrix formation, migration and stemness, including TNC (Garcion et al, 2004), PTPRZ1 (Baldauf et al, 2015), FAM107A (Kiwerska et al, 2017), HOPX (Yap et al, 2016), and LIFR (Wu et al, 2018). Importantly, LIFR/STAT3 signaling was found to be required for bRG cell cycle progression and selectively expressed by bRGs (Pollen et al, 2015).…”

The Stress-Inducible Protein DRR1 Exerts Distinct Effects on Actin Dynamics

“…It is also known as Tohoku University cDNA clone A on chromosome 3 (TU3A) or Family with sequence similarity 107, member A (FAM107A) [24,25]. DRR1 is downregulated in various cancer cell lines, including renal cell, ovarian, cervical, laryngeal, gastric, prostate, liver, lymph, and non-small cell lung cancer and is associated with the progression of neuroblastoma, meningioma and malignant glioma [26,27,28,29,30,31,32,33,34,35,36]. On the other hand, DRR1 is highly expressed in outer radial glial cells [37] and in the invasive component of glioblastoma [38,39].…”

Recurrent transcriptional loss of the PCDH17 tumor suppressor in laryngeal squamous cell carcinoma is partially mediated by aberrant promoter DNA methylation

“…LSCC cell lines ( n = 16) established at the Turku University Central Hospital (Finland) and previously cytogenetically characterized, were used in this study (Supplementary Table S1A). Cell culture conditions and further characteristics can be found elsewhere …”

“…The cell lines were incubated with 0.1 µM and 0.3 µM DAC concentrations in the culture medium and, as the control the same cell lines were incubated with the same volume of 50% acetic acid (aa) (solvent used to prepare DAC dilutions). Detailed description of the procedure was published recently . The demethylation experiments with decitabine were performed in duplicates for UT‐SCC‐11 and triplicates for UT‐SCC‐29 cell lines.…”

“…Cell culture conditions and further characteristics can be found elsewhere. 10 Primary LSCC tumor biopsies (n = 81) ( Supplementary Table S1B Table S1C).…”