Lactotransferrin: A candidate tumor suppressor—Deficient expression in human nasopharyngeal carcinoma and inhibition of NPC cell proliferation by modulating the mitogen‐activated protein kinase pathway

Abstract

Lactotransferrin (LTF) has been shown to regulate tumorogenesis. However, little is known about the role of LTF in regulating the development of human nasopharyngeal carcinoma (NPC). The aim of our study was to investigate whether LTF could regulate the development of NPC by characterizing the pattern of LTF expression in human NPC tissues using cDNA and tissue microarrays. Loss of LTF expression was observed in a significantly higher frequency of NPC tissues compared to that in nontumor nasopharyngeal epithelial tissues. While 61.25% of NPC tissues at the T1/T2 stage were positive for LTF expression, only 40.82% of NPC at the T3/T4 stage were stained by anti-LTF. Similarly, 41.58% of NPC with local lymph node metastasis displayed LTF expression, a value significantly lower than the 46.36% in primary tumors (p < 0.05). These findings suggest that LTF may negatively regulate the development and metastasis of NPC in vivo. Furthermore, overexpression of or treatment with LTF inhibited the proliferation of NPC cells and promoted cell cycle arrest at the G 0 /G 1 phase in vitro. While LTF treatment downregulated expression of cyclin D1 and phosphorylation of retinoblastoma protein (Rb), expression of p21 and p27 in 5-8F NPC cells was enhanced. Moreover, LTF treatment modulated the mitogen-activated protein kinase (MAPK) pathway, but did not affect p53 and STAT3 expression in 5-8F NPC cells. Thus LTF is likely to be a candidate tumor suppressor and downregulates the development of NPC by inhibiting NPC proliferation through induction of cell cycle arrest and modulation of the MAPK signaling pathway. Therefore, our findings provide new insights in understanding the mechanism(s) underlying the action of LTF in regulating the development of human NPC.

Lactoferrin suppresses the Epstein–Barr virus-induced inflammatory response by interfering with pattern recognition of TLR2 and TLR9

“…24 We previously observed a notable reduction of LF in NPC tissues and identified it as a candidate tumor suppressor for NPC. Our subsequent studies showed that LF inhibits NPC cell proliferation, induces cell cycle G 1 /S arrest, modulating MAPK signaling pathway, and cyclin D1-related proteins, 20 and inhibits NPC metastasis by suppressing AKT activity. 25 EBV is widespread in human populations, and EBV infection has been linked to the tumorigenesis of multiple cancers including NPC.…”

“…20 Nuclear protein was isolated with nuclear and cytoplasmic Extraction Kit (Thermo Fisher Scientific, Waltham, MA, USA). Antibodies against p65, GAPDH and CD14 were obtained from Santa Cruz Biotechnology.…”

“…19 Further isolation and identification of a list of new tumor-suppressor genes for NPC from this region were pursued and LF gene is one of the candidates. 20 By means of cDNA microarray analysis, we found that LF mRNA levels were significantly downregulated in NPC tissues and that its expression levels were negatively correlated with the expression levels of inflammatory cytokines, such as IL-8 (unpublished data). More recently, we reported that LF could protect human primary B lymphocytes from EBV infection by binding directly to the EBV receptor CD21 on the B-cell surface.…”

MiR-663, a microRNA targeting p21WAF1/CIP1, promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma

“…For example, as mentioned above, there are multiple miRNAs directly regulated p21 in the literature. Notably, various factors, such as the EBV nuclear antigen 2 and lactotransferrin, have been reported to regulate p21 in NPC (Lin et al, 2000;Zhou et al, 2008).…”

Lactoferrin increases 172ThrAMPK phosphorylation and insulin-induced p473SerAKT while impairing adipocyte differentiation

“…16 Lactoferrin also participates in the regulation of cellular growth and differentiation. 17,18 In primary osteoblasts, lactoferrin stimulated proliferation and differentiation and even acted as a survival factor, thereby, inhibiting apoptosis induced by serum withdrawal and also inhibiting osteoclastogenesis in a murine bone marrow culture. 19 To the best of our knowledge, effects of lactoferrin on the response to insulin (through p473Ser AKT) have never been explored.…”