Complement C3 overexpression activates JAK2/STAT3 pathway and correlates with gastric cancer progression

Abstract

Background: Localized C3 deposition is a well-known factor of inflammation. However, its role in oncoprogression of gastric cancer (GC) remains obscured. This study aims to explore the prognostic value of C3 deposition and to elucidate the mechanism of C3-related oncoprogression for GC. Methods: From August to December 2013, 106 GC patients were prospectively included. The regional expression of C3 and other effectors in gastric tissues were detected by WB, IHC, qRT-PCR and other tests. The correlation of localized C3 deposition and oncologic outcomes was determined by 5-year survival significance. Human GC and normal epithelial cell lines were employed to detect a relationship between C3 and STAT3 signaling pathway in vitro experiments. Results: C3 and C3a expression were markedly enhanced in GC tissues at both mRNA and protein levels compared with those in paired nontumorous tissues. According to IHC C3 score, 65 (61.3%) and 41 (38.7%) patients had high and low C3 deposition, respectively. C3 deposition was negatively correlated with plasma levels of C3 and C3a (both P < 0.001) and positively correlated with pathological T and TNM stages (both P < 0.001). High C3 deposition was identified as an independent prognostic factor of poor 5-year overall survival (P = 0.045). In vitro C3 administration remarkably enhanced p-JAK2/p-STAT3 expression in GC cell lines but caused a reduction of such activation when pre-incubated with a C3 blocker. Importantly, C3 failed to activate such signaling in cells pretreated with a JAK2 inhibitor.Conclusions: Localized C3 deposition in the tumor microenvironment is a relevant immune signature for predicting prognosis of GC. It may aberrantly activate JAK2/STAT3 pathway allowing oncoprogression.

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

“…(ii) Autocrine regulation of complement transcripts/secretion by complement complexes or cleavage products, which are only produced if the SNP is present, could be imaginable. Complement components or complement cleavage products can activate cellular signaling pathways via specific receptors [ 63 , 64 , 65 ], which can result in increased or reduced transcription of complement components by associated transcription factors [ 66 , 67 , 68 ]. As we showed the secretion of complement components and presents of complement activation products as well as of receptors in hpRPE cells an autocrine regulation of complement is speculatively possible.…”

Complement in Tumourigenesis and the Response to Cancer Therapy

“…Altered protein expression of complement components has also been described. In gastric cancer, tumours exhibit enhanced deposition of C3 and C3a relative to adjacent healthy tissue, with high C3 deposition observed to correlate with worse 5 year OS [155]. Evidence suggests that C3 deposits may activate JAK2/STAT3 to enhance tumour growth [155].…”

The underlying molecular mechanism and drugs for treatment in adrenal cortical carcinoma

“…Yuan et al study found that high complement C3 (C3) deposition activates JAK2/STAT3 pathway correlates with in gastric cancer progression and was identified as an independent prognostic factor of poor overall survival [22]. C3 plays a role of diagnostic signature including achieved a predictive error of 12.8% and a Generalized Brier Score of 0.108 lung adenocarcinoma and squamous cell carcinoma [23].…”