Abstract
Human endogenous retroviruses (HERVs) are suggested to be involved in the development of certain diseases, especially cancers. To elucidate the function of HERV-K Env protein in cancers, an HERV-K env gene knockout (KO) in DLD-1 colorectal cancer cell lines was generated using the CRISPR-Cas9 system. Transcriptome analysis of HERV-K env KO cells using next-generation sequencing (NGS) was performed to identify the key genes associated with the function of HERV-K Env protein. The proliferation of HERV-K env KO cells was significantly reduced in in vitro culture as well as in in vivo nude mouse model. Tumorigenic characteristics, including migration, invasion, and tumor colonization, were also significantly reduced in HERV-K env KO cells. Whereas, they were enhanced in HERV-K env over-expressing DLD-1 cells. The expression of nuclear protein-1 (NUPR1), an ER-stress response factor that plays an important role in cell proliferation, migration, and reactive oxygen species (ROS) generation in cancer cells, significantly reduced in HERV-K env KO cells. ROS levels and ROS-related gene expression was also significantly reduced in HERV-K env KO cells. Cells transfected with NUPR1 siRNA (small interfering RNA) exhibited the same phenotype as HERV-K env KO cells. These results suggest that the HERV-K env gene affects tumorigenic characteristics, including cell proliferation, migration, and tumor colonization through NUPR1 related pathway.
Highlights
In order to identify the function of the Human endogenous retroviruses (HERVs)-K env gene in tumorigenic characteristics in colorectal cancer, HERV-K env knockout (KO) DLD-1 colorectal cancer cell lines were generated using the CRISPR-Cas9 gene editing system
HERV-K Env protein expression was analyzed by Western blot and immunostaining
Comparing the mean size of total tumors, tumor growth was significantly reduced or the tumor was not formed in the HERV-K env KO injected group, being significantly increased in the HERV-K env over-expressing cells injected group. These results showed that tumor growth is significantly related to HERV-K env genes in vivo
Summary
The vertebrate genome contains an endogenous retrovirus that inherited parts millions of years ago. Approximately 8% of human chromosomal DNA consists of sequences derived from human endogenous retrovirus (HERV) fragments, most HERVs are currently inactive and non-infectious due to recombination, deletions, and mutations after insertion into the host genome [1,2]. HERVK elements have been reported to be transcribed and expressed as proteins in certain diseases, including cancer. HERV-K hypomethylation in ovarian clear cell carcinoma has been reported to be associated with a poor prognosis and platinum resistance [14]. We previously reported that the expression of HERV-K Env protein was higher in various cancers than in normal tissues [16]
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