Urotensin II contributes to the formation of lung adenocarcinoma inflammatory microenvironment through the NF-κB pathway in tumor-bearing nude mice

Abstract

Abstract. Urotensin II (UII), a somatostatin-like cyclic peptide, was originally isolated from the fish urophysis. Our previous study showed that UII stimulates the proliferation of A549 lung adenocarcinoma cells and promotes tumor growth in a nude mouse xenograft model, suggesting that UII may contribute to the pathogenesis of lung adenocarcinoma. In this study, the underlying mechanism for UII to promote lung adenocarcinoma growth was explored by observing the effect of UII on the tumor inflammatory microenvironment in tumor-bearing nude mice. Immunohistochemical analysis showed that UII promoted the infiltration of CD68 + tumor-associated macrophages (TAMs) in the tumor microenvironment. Enzyme-linked immunosorbent assay (ELISA) demonstrated that UII promoted the release of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9). Western blot analysis showed that UII promoted the activation of nuclear factor-κB (NF-κB). These findings suggest that the enhanced levels of IL-6, TNF-α and MMP-9 in the tumor microenvironment, which likely resulted from increased activation of NF-κB induced by UII, may be one of the important mechanisms by which UII promotes lung adenocarcinoma growth. These findings imply that antagonists of UII or urotensin II-receptor (UT-R) have potential for the prevention and treatment of lung adenocarcinoma. IntroductionSeveral lines of evidence have suggested a strong association between chronic inflammation and carcinogenesis (1-4). It has been estimated that up to 20% of all tumors arise from the sites of infection, chronic irritation and inflammation (1). Persistent stimulation of chronic inflammation may cause the infiltration of inflammatory cells, the release of cytokines and the production of reactive oxygen species, which results in DNA damage, angiogenesis, tumor invasion and metastasis (1). There are numerous types of inflammatory cells in the tumor microenvironment, and tumor-associated macrophages (TAMs) are a major component. While the role of TAMs in tumor development is complex and multifaceted, in clinical studies, increased TAM density has been found to be associated with poor prognosis (5-7). TAMs contribute to tumor development through several mechanisms, including releasing angiogenic factors, promoting tumor cell proliferation, and facilitating tumor cell invasion and metastasis (8).Lung cancer is one of the models of inflammation-driven carcinogenesis (9,10). It has been shown that chronic exposure to tobacco smoke is the major risk factor for development of lung cancer by inducing inflammation (11,12). Takahashi et al (13) further demonstrated that tobacco smoke promotes lung tumorigenesis by triggering IKKβ-and JNK1-dependent inflammation. Moreover, regular use of nonsteroidal antiinflammatory drugs decreases the risk of lung cancer (14,15). Therefore, inflammation plays an important role in lung carcinogenesis.Urotensin II (UII), a somatostatin-like cyclic peptide, was originally isolated from the fish urophysis (16). Subseque...

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

“…Both UT mRNA and UT protein are present in human lung adenocarcinoma A549 cells and exogenous UII activates proliferation of these cells in vitro and in vivo (Wu et al, 2010). UII-evoked lung adenocarcinoma growth is likely mediated through the nuclear factor kB pathway (Zhou et al, 2012). Abundant expression of UT mRNA and UT protein is observed in the interstitial nodular lesions of patients with lymphangioleiomyomatosis, whereas UT mRNA is not expressed in normal human lungs (Kristof et al, 2010).…”

“…Immunoreactive UII and URP are present in interstitial nodular lesions of lungs from patients with lymphangioleiomyomatosis, a rare disease characterized by abnormal proliferation of smooth muscle-like cells in the pulmonary interstitium (Kristof et al, 2010). UII promotes lung adenocarcinoma growth via a mechanism involving activation of the nuclear factor kB pathway and a proinflammatory microenvironment (Zhou et al, 2012).…”

Urotensin II upregulates migration and cytokine gene expression in leukocytes of the African clawed frog, Xenopus laevis

“…It is well known that NF-jB in mammals plays a critical role in the activation of immune cells by upregulating the expression of many cytokines (e.g., IL-1, IL-2, IL-6, IL-12, TNF-a, IFN-c, and GM-CSF) essential to the immune response (Liang et al, 2013). UII increased the phosphorylation of NF-jB in lung adenocarcinoma A549 cells and induced the upregulation of cytokines such as IL-6 and TNFa (Zhou et al, 2012). Furthermore, the mutation of NF-jB binding sites on the IL-8 promoter reduced promoter activity in human umbilical vein endothelial cells, suggesting that the NF-jB transcription factor plays key roles in the induction of IL-8 expression (Lee et al, 2014).…”

Increased expression of urotensin II is associated with poor prognosis in hepatocellular carcinoma

“…UII is a somatostatin-like cyclic undecapeptide that has been identified as a potent mammalian vasoconstrictor (15). As well as affecting vascular tone, UII stimulates cell proliferation, and previous studies have indicated that is involved in the pathogenesis of certain tumors, including breast, bladder, colon and prostate cancer (12–14,28). Our previous study demonstrated that the expression of the UII/UT system was increased in HCC tissues and cell lines, and that exogenous administration of UII regulated the proliferation of cancer cells and increased the expression of various transcription factors, including ERK, PKC and p38 MAPK (18,20).…”