Transposon mutagenesis screen in mice identifies TM9SF2 as a novel colorectal cancer oncogene

Abstract

New therapeutic targets for advanced colorectal cancer (CRC) are critically needed. Our laboratory recently performed an insertional mutagenesis screen in mice to identify novel CRC driver genes and, thus, potential drug targets. Here, we define Transmembrane 9 Superfamily 2 (TM9SF2) as a novel CRC oncogene. TM9SF2 is an understudied protein, belonging to a well conserved protein family characterized by their nine putative transmembrane domains. Based on our transposon screen we found that TM9SF2 is a candidate progression driver in digestive tract tumors. Analysis of The Cancer Genome Atlas (TCGA) data revealed that approximately 35% of CRC patients have elevated levels of TM9SF2 mRNA, data we validated using an independent set of CRC samples. RNAi silencing of TM9SF2 reduced CRC cell growth in an anchorage-independent manner, a hallmark of cancer. Furthermore, CRISPR/Cas9 knockout of TM9SF2 substantially diminished CRC tumor fitness in vitro and in vivo. Transcriptome analysis of TM9SF2 knockout cells revealed a potential role for TM9SF2 in cell cycle progression, oxidative phosphorylation, and ceramide signaling. Lastly, we report that increased TM9SF2 expression correlates with disease stage and low TM9SF2 expression correlate with a more favorable relapse-free survival. Taken together, this study provides evidence that TM9SF2 is a novel CRC oncogene.

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

“…RNAs derived from SH4 with (#4 and #5) or without (Mock; two samples) B4GALNT1 over-expression were analyzed by RNA sequencing as described in ref. [76][77][78] . Quality tested with Bioanalyzer 2100 (Agilent Technologies, USA).…”

Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study

“…DMRs associated with PFOA were also annotated to NR1H2, involved in lipid homeostasis and inflammation; and RPTOR, part of the mTOR complex that regulates cell growth in response to nutrient availability. Other genes that were associated with multiple PFAS include RNF39, a gene within the major histocompatibility complex class 1 region on chromosome 6 associated with early synaptic plasticity and previously linked with multiple sclerosis (Maltby et al 2017); RASL11B, a widely expressed gene with proposed roles in inflammation and arteriosclerosis (Stolle et al 2007); and TM9SF2, encoding a transmembrane protein and reported to be a colorectal cancer oncogene (Clark et al 2018).…”

LINC01232 exerts oncogenic activities in pancreatic adenocarcinoma via regulation of TM9SF2

“…TM9SF2 is an evolutionarily conserved transmembrane protein and has been identified as a glycolipid-regulating factor and a novel colorectal cancer oncogene 14,26 . However, the function of TM9SF2 in tumorigenesis and progression of PAAD still needs to be delineated.…”

“…In our current study, we identified that LINC01232 positively regulated its nearby gene transmembrane 9 superfamily member 2 (TM9SF2). A recent study has indicated that TM9SF2 acts as a novel oncogene in colorectal cancer 14 . Nevertheless, the participation of TM9SF2 in pancreatic carcinoma progression is vague.…”