Neuropeptide Y1 receptor inhibits cell growth through inactivating mitogen-activated protein kinase signal pathway in human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers, and its incidence is increasing worldwide. Neuropeptide Y (NPY) broadly expressed in the central and peripheral nervous system. It participates in multiple physiological and pathological processes through specific receptors. Evidences are accumulating that NPY is involved in development and progression in neuro- or endocrine-related cancers. However, little is known about the potential roles and underlying mechanisms of NPY receptors in HCC. In this study, we analyzed the expression of NPY receptors by real-time polymerase chain reaction, Western blot, and immunohistochemical staining. Correlation between NPY1R levels and clinicopathological characteristics, and survival of HCC patients were explored, respectively. Cell proliferation was researched by CCK-8 in vitro, and tumor growth was studied by nude mice xenografts in vivo. We found that mRNA and protein level of NPY receptor Y1 subtype (NPY1R) significantly decreased in HCC tissues. Low expression of NPY1R closely correlated with poor prognosis in HCC patients. Proliferation of HCC cells was significantly inhibited by recombinant NPY protein in vitro. This inhibitory effect could be blocked by selected NPY1R antagonist BIBP3226. Furthermore, overexpression of NPY1R could significantly inhibit HCC cell proliferation. Knockdown of NPY1R promoted cell multiplication in vitro and increased tumorigenicity and tumor growth in vivo. NPY1R was found to participate in the inhibition of cell proliferation via inactivating mitogen-activated protein kinase signal pathway in HCC cells. Collectively, NPY1R plays an inhibitory role in tumor growth and may be a promising therapeutic target for HCC.

Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer

“…Conversely, we found that non-Y5 NPY receptors (Y1R and Y2R) were downregulated and did not have tumor-promoting functions in HCC. Actually, Y1R even revealed suppressive effects on tumor cell migration, which is in accordance with the only study that investigated the potential function of an NPY receptor in liver cancer so far (87). In line with our findings, Lv et al observed that Y1R is downregulated in HCC and that forced overexpression of Y1R mediates tumor suppressor functions in HCC cells (87).…”

“…Actually, Y1R even revealed suppressive effects on tumor cell migration, which is in accordance with the only study that investigated the potential function of an NPY receptor in liver cancer so far (87). In line with our findings, Lv et al observed that Y1R is downregulated in HCC and that forced overexpression of Y1R mediates tumor suppressor functions in HCC cells (87). In contrast to this single study on Y1R function, the potential roles of NPY, Y2R, and Y5R in HCC had been entirely unknown.…”

Transcriptome profiling identified differentially expressed genes and pathways associated with tamoxifen resistance in human breast cancer

“…Eftang LL et al reported that the GFRA3 promoter region was found to be hypermethylatied in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance [ 24 ]. NPY1R was found to participate in the inhibition of cell proliferation via inactivating mitogen-activated protein kinase signal pathway in HCC cells and play an inhibitory role in tumor growth [ 25 , 26 ]. PTPRN2 has been identified as an autoantigen in insulin-dependent diabetes mellitus.…”

Genes encoding neuropeptide receptors are epigenetic markers in patients with head and neck cancer: a site-specific analysis

“…NPY regulates food intake, blood pressure, and circadian rhythms, as well as other physiological activities [ 19 ]. Via NPY1R, NPY inhibits the growth of hepatocellular carcinomas by inactivating the mitogen-activated protein kinase signaling pathway [ 20 ]. Significant associations between cumulative arsenic exposure and the methylation level of the NPY2R gene have been observed in smoking-unrelated urothelial carcinomas [ 21 ].…”