Although mounting evidence has demonstrated that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) can promote tumorigenesis, its role in cancer remains controversial. To find potential target molecules of PGC-1α, GeneFishingTM DEG (differentially expressed genes) screening was performed using stable HEK293 cell lines expressing PGC-1α (PGC-1α-HEK293). As results, leucyl-tRNA synthetase 1 (LARS1) was upregulated. Western blot analysis showed that LARS1 was increased in PGC-1α overexpressed SW480 cells but decreased in PGC-1α shRNA knockdown SW620 cells. Several studies have suggested that LARS1 can be a potential target of anticancer agents. However, the molecular network of PGC-1α and LARS1 in human colorectal cancer cells remains unclear. LARS1 overexpression enhanced cell proliferation, migration, and invasion, whereas LARS1 knockdown reduced them. We also observed that expression levels of cyclin D1, c-Myc, and vimentin were regulated by LARS1 expression. We aimed to investigate whether effects of PGC-1α on cell proliferation and invasion were mediated by LARS1. Our results showed that PGC-1α might modulate cell proliferation and invasion by regulating LARS1 expression. These results suggest that LARS1 inhibitors might be used as anticancer agents in PGC-1α-overexpressing colorectal cancer. Further studies are needed in the future to clarify the detailed molecular mechanism by which PGC-1α regulates LARS1 expression.

The prognosis of patients with colorectal cancer (CRC) is affected by invasion and metastasis. Leucyl-tRNA synthetase (LARS) was shown to be related to the growth and migration of lung cancer cells. Dickkopf 4 (DKK4) is known as a Wnt/β-catenin pathway inhibitor, and its upregulation was reported in several cancers. However, the clinical significance of LARS and DKK4 in human CRC has not been clearly defined. We investigated the expression of LARS and DKK4 by immunohistochemical staining in tissue microarrays from 642 primary CRC patients and analyzed the relationship between their expression and the clinicopathological characteristics of CRC patients. LARS and DKK4 expressions were not related to gender, age at surgery, histologic grade, size, tumor location, tumor invasion, or metastasis, but LARS expression was significantly correlated with TNM stage, N stage, and lymph node metastasis. DKK4 expression was inversely related to the TNM stage and N stage. Survival analysis demonstrated that the OS and DFS in the LARS high expression group were not different compared to the LARS low expression group. OS and DFS in the DKK4 high expression group were significantly higher than in the DKK4 low expression group. In addition, OS and DFS in the group with the combination of the LARS high/DKK4 low expression were significantly lower than in the LARS high/DKK4 high expression group. The low expression of DKK4 alone can be used as a predictor of relapse in CRC patients. In addition, DKK4 low expression in the case of LARS high expression can be used as a poor prognostic factor in CRC patients. Thus, our findings suggest that DKK4 alone or in combination with LARS at diagnosis may be a useful prognostic factor for CRC.