C5aR is frequently expressed in metastatic renal cell carcinoma and plays a crucial role in cell invasion via the ERK and PI3 kinase pathways

Maeda, Yoshihiro; Kawano, Yoshiaki; Wada, Yasuhiko; Yatsuda, Junji; Motoshima, Takanobu; Murakami, Yoji; Kikuchi, Ken; Imamura, Takahisa; Eto, Masatoshi

doi:10.3892/or.2015.3800

Cited by 39 publications

(38 citation statements)

References 29 publications

(36 reference statements)

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“…However, C5aR is universally expressed, especially in cancer cells [18, 22], and another mechanism of direct interaction of C5a with C5aR on cancer cells is somewhat underestimated. In fact, cancer malignancy could be enhanced directly by C5a via tumoral C5aR, instead of being mediated by thirdparty [11, 18]. In this study, high C5a level did not always guarantee a worse prognosis, but enrichment of C5a-C5aR axis did.…”

Section: Discussionmentioning

confidence: 56%

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Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma

Liu

Wang

et al. 2016

Oncotarget

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Anaphylatoxin C5a and its receptor C5aR on cancer cells constitute a vital axis to cancer progression. In this study, we measured C5aR level by immunohistochemistry in the same cohort of our previous C5a research, and C5a-C5aR axis status was determined by synthesizing C5a and C5aR data. C5aR was an adverse independent prognostic factor for ccRCC patients. Kaplan-Meier analyses revealed the unique position of both C5a and C5aR high population in postoperative survival, based on which patients were then shunted into C5a-C5aR enriched and non-enriched groups. Obviously, C5a-C5aR enriched patients significantly had a poorer overall survival (OS) and recurrence free survival (RFS) compared with non-enriched ones, and the independence of C5a-C5aR axis was verified by multivariable analyses (HR 2.118, P = 0.001 for OS, HR 1.715, P = 0.035 for RFS). Established nomograms based on our findings reflected much better predicting accuracy in contrast with most common used TNM and Fuhrman systems. Meanwhile, consistent with HR, C5a-C5aR axis in this study held its advantages over C5a and C5aR for OS prediction by c-index analyses, rather than RFS prediction.

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Section: Discussionmentioning

confidence: 56%

“…Complement system has been found to have a vital impact on tumor initiation and progression, and anaphylatoxin C5a and its receptor C5aR on cancer cells constitute a vital axis [9–11]. However, seldom studies investigated into the relationship between this axis and clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma

Liu

Wang

et al. 2016

Oncotarget

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“…Reportedly, C5a can trigger MAPK activation in some target cells [41–43] and MAPK signal pathways are involved in mediating cellular IL-6 and TNF-α production [41, 44–47]. As a result, the regulatory roles of MAPK signaling pathways in C5a-induced IL-6 and TNF-α expression in the GMC were further explored in the present studies.…”

Section: Discussionmentioning

confidence: 96%

C5a Induces the Synthesis of IL-6 and TNF-α in Rat Glomerular Mesangial Cells through MAPK Signaling Pathways

Zhao

et al. 2016

PLoS ONE

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Inflammatory response has been reported to contribute to the renal lesions in rat Thy-1 nephritis (Thy-1N) as an animal model of human mesangioproliferative glomerulonephritis (MsPGN). Besides C5b-9 complex, C5a is also a potent pro-inflammatory mediator and correlated to severity of various nephritic diseases. However, the role of C5a in mediating pro-inflammatory cytokine production in rats with Thy-1N is poorly defined. In the present studies, the levels of C5a, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were first determined in the renal tissues of rats with Thy-1N. Then, the expression of IL-6 and TNF-α was detected in rat glomerular mesangial cells (GMC) stimulated with our recombinant rat C5a in vitro. Subsequently, the activation of mitogen-activated protein kinase (MAPK) signaling pathways (p38 MAPK, ERK1/2 and JNK) and their roles in the regulation of IL-6 and TNF-α production were examined in the GMC induced by C5a. The results showed that the levels of C5a, IL-6 and TNF-α were markedly increased in the renal tissues of Thy-1N rats. Rat C5a stimulation in vitro could up-regulate the expression of IL-6 and TNF-α in rat GMC, and the activation of MAPK signaling pathways was involved in the induction of IL-6 and TNF-α. Mechanically, p38 MAPK activation promoted IL-6 production, while either ERK1/2 or JNK activation promoted TNF-α production in the GMC with exposure to C5a. Taken together, these data implicate that C5a induces the synthesis of IL-6 and TNF-α in rat GMC through the activation of MAPK signaling pathways.

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“…Inflammation is a contributor to NSCLC progression [10–12], and C5a can cause tumor cell proliferation [8, 9, 28, 29]. However, how C5a affects tumor cell proliferation in NSCLC still remains obscure.…”

Section: Discussionmentioning

confidence: 99%

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

Zhao

Qiu

et al. 2018

Oncogene

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (−103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5–GCN5–GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.

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C5aR is frequently expressed in metastatic renal cell carcinoma and plays a crucial role in cell invasion via the ERK and PI3 kinase pathways

Cited by 39 publications

References 29 publications

Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma

Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma

C5a Induces the Synthesis of IL-6 and TNF-α in Rat Glomerular Mesangial Cells through MAPK Signaling Pathways

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

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