ZFR promotes cell proliferation and tumor development in colorectal and liver cancers

Colorectal cancer (CRC) and liver cancer are the second and fourth leading causes of cancer-related deaths in the whole world, respectively, and each year over 1.6 million people die from these diseases. To identify driver genes in CRC and liver cancer, we have performed Sleeping Beauty transposon mutagenesis screens in mouse models. Zinc finger RNA binding protein, ZFR, was one of the novel candidate cancer genes identified in these forward genetic screens. Consistent with this discovery, a pan-cancer analysis of sequencing results of thousands of human cancer genomes demonstrated that ZFR is a potential potent oncogene. In this study, we aimed to investigate ZFR's roles in both types of cancer and found that overexpression of ZFR in CRC and liver cancer cells led to accelerated tumor development. Consistently, knockdown of ZFR resulted in significantly decelerated tumor development. ZFR overexpression also promoted tumor development of immortalized mouse liver cells. ZFR overexpression and shRNA knockdown led to accelerated and decelerated cell proliferation, respectively, indicating that ZFR promotes tumor development mainly by regulating cell proliferation. To identify ZFR's targets in transcription, we performed whole transcriptome sequencing using ZFR small interfering RNAs in a primary human colon cell line. All potential target genes were validated by real time PCR. FAM49B was a tumor suppressor candidate for ZFR targets. When we knocked down the expression of FAM49B in CRC and liver cancer cells, we observed significantly accelerated cell proliferation, consistent with the results with ZFR overexpression. The results presented here demonstrate the oncogenic role of ZFR in both CRC and liver cancer, providing a potential drug target for both cancers' treatment. We also identified ZFR's potential transcriptional targets, and further investigations on those targets, especially FAM49B, will help us understand more about the important role of ZFR in digestive system cancers.