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.

中文翻译：

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小鼠中的转座子诱变筛选将TM9SF2鉴定为一种新型的结直肠癌致癌基因。

迫切需要用于晚期结直肠癌（CRC）的新治疗靶标。我们的实验室最近在小鼠中进行了插入诱变筛选，以鉴定新的CRC驱动基因，从而确定潜在的药物靶标。在这里，我们将跨膜9超家族2（TM9SF2）定义为新型CRC癌基因。TM9SF2是一种尚未被充分研究的蛋白质，属于一个以9个推定跨膜结构域为特征的高度保守的蛋白质家族。根据我们的转座子筛选，我们发现TM9SF2是消化道肿瘤的候选进展驱动因素。癌症基因组图谱（TCGA）数据的分析显示，大约35％的CRC患者的TM9SF2 mRNA水平升高，我们使用一组独立的CRC样本验证了这些数据。TM9SF2的RNAi沉默以锚定非依赖性方式降低CRC细胞的生长，癌症的标志。此外，TM9SF2的CRISPR / Cas9敲除大大降低了体外和体内CRC肿瘤的适应性。TM9SF2敲除细胞的转录组分析显示TM9SF2在细胞周期进程，氧化磷酸化和神经酰胺信号传导中的潜在作用。最后，我们报道增加的TM9SF2表达与疾病分期相关，而较低的TM9SF2表达与更有利的无复发生存率相关。两者合计，这项研究提供了证据，证明TM9SF2是一种新型的CRC癌基因。我们报告说增加的TM9SF2表达与疾病分期相关，而较低的TM9SF2表达与更有利的无复发生存率相关。两者合计，这项研究提供了证据，证明TM9SF2是一种新型的CRC癌基因。我们报告说增加的TM9SF2表达与疾病分期相关，而较低的TM9SF2表达与更有利的无复发生存率相关。两者合计，这项研究提供了证据，证明TM9SF2是一种新型的CRC癌基因。