Prognostic value and biological function of LRRN4 in colorectal cancer

Abstract

Background Several nervous and nerve-related biomarkers have been detected in colorectal cancer (CRC) and can contribute to the progression of CRC. However, the role of leucine-rich repeat neuronal 4 (LRRN4), a recently identified neurogenic marker, in CRC remains unclear. Methods We examined the expression and clinical outcomes of LRRN4 in CRC from TCGA-COREAD mRNA-sequencing datasets and immunohistochemistry in a Chinese cohort. Furthermore, colony formation, flow cytometry, wound healing assays and mouse xenograft models were used to investigate the biological significance of LRRN4 in CRC cell lines with LRRN4 knockdown or overexpression in vitro and in vivo. In addition, weighted coexpression network analysis, DAVID and western blot analysis were used to explore the potential molecular mechanism. Results We provide the first evidence that LRRN4 expression, at both the mRNA and protein levels, was remarkably high in CRC compared to controls and positively correlated with the clinical outcome of CRC patients. Specifically, LRRN4 was an independent prognostic factor for progression-free survival and overall survival in CRC patients. Further functional experiments showed that LRRN4 promoted cell proliferation, cell DNA synthesis and cell migration and inhibited apoptosis. Knockdown of LRRN4 can correspondingly decrease these effects in vitro and can significantly suppress the growth of xenografts. Several biological functions and signaling pathways were regulated by LRRN4, including proteoglycans in cancer, glutamatergic synapse, Ras, MAPK and PI3K. LRRN4 knockdown resulted in downregulation of Akt, p-Akt, ERK1/2 and p-ERK1/2, the downstream of the Ras/MAPK signaling pathway, overexpression of LRRN4 leaded to the upregulation of these proteins. Conclusions Our results suggest that LRRN4 could be a biological and molecular determinant to stratify CRC patients into distinct risk categories, and mechanistically, this is likely attributable to LRRN4 regulating several malignant phenotypes of neoplastic cells via RAS/MAPK signal pathways.

Leukotriene B4 receptor knockdown affects PI3K/AKT/mTOR signaling and apoptotic responses in colorectal cancer

“…For instance, Yuan et al [ 34 ] previously demonstrated that differential expression of INHBB significantly influences the prognosis of CRC patients and is associated with various oncogenic signaling pathways. Similarly, Xu et al [ 35 ] reported that LRRN4 modulates the malignant phenotype of CRC tumor cells through the rat sarcoma (RAS)/MAPK signaling pathway. Another study highlighted that overexpression of FSTL3 impacts CRC prognosis and can promote epithelial-to-mesenchymal transition (EMT) and aerobic glycolysis via the activated β-catenin pathway, thereby affecting CRC cell invasiveness and metastatic capability [ 36 ].…”

Network pharmacology and molecular docking to elucidate the mechanism of pulsatilla decoction in the treatment of colon cancer

“…Alterations in the MAPK signaling pathway are strongly associated with the progression of colon cancer cells ( Burotto et al, 2014 ). Xu C et al demonstrated that altering the expression of ERK1/2 and Akt genes downstream of the MAPK signaling pathway regulates DNA synthesis, proliferation, and apoptosis in colon cancer cells ( Xu C. et al, 2022 ). Ma W et al downregulated the phosphorylated expression of MEK1/2, ERK1/2, and RAF1 in the MAPK signaling pathway as a way to regulate the malignant proliferating phenotype of colon tumors ( Ma et al, 2021 ).…”