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Human endogenous retrovirus (HERV)-K was reportedly inserted into the human genome millions of years ago and is closely related to various diseases, including cancer and immune regulation. In our previous studies, CRISPR-Cas9-enabled knockout (KO) of the HERV-K <i>env</i> gene was found to potentially reduce cell proliferation, cell migration, and invasion in colorectal and ovarian cancer cell lines. The immune response involves the migration and invasion of cells and is similar to cancer; however, in certain ways, it is completely unlike cancer. Therefore, we induced HERV-K119 <i>env</i> gene KO in THP-1, a monocytic cell that can be differentiated into a macrophage, to investigate the role of HERV-K119 <i>env</i> in immune regulation. Cell migration and invasion were noted to be significantly increased in HERV-K119 <i>env</i> KO THP-1 cells than in MOCK, and these results were contrary to those of cancer cells. To identify the underlying mechanism of HERV-K119 <i>env</i> KO in THP-1 cells, transcriptome analysis and cytokine array analysis were conducted. Semaphorin7A (SEMA7A), which induces the production of cytokines in macrophages and monocytic cells and plays an important role in immune effector cell activation during an inflammatory immune response, was significantly increased in HERV-K119 <i>env</i> KO THP-1 cells. We also found that HERV-K119 <i>env</i> KO THP-1 cells expressed various macrophage-specific surface markers, suggesting that KO of HERV-K119 <i>env</i> triggers the differentiation of THP-1 cells from monocytic cells into macrophages. In addition, analysis of the expression of M1 and M2 macrophage markers showed that M1 macrophage marker cluster of differentiation 32 (CD32) was significantly increased in HERV-K119 <i>env</i> KO cells. These results suggest that HERV-K119 <i>env</i> is implicated in the differentiation of monocytic cells into M1 macrophages and plays important roles in the immune response.