Upregulation of IL-11, an IL-6 Family Cytokine, Promotes Tumor Progression and Correlates with Poor Prognosis in Non-Small Cell Lung Cancer

Abstract

Background/Aims: Cytokines are key players in tumorigenesis and are potential targets in cancer treatment. Although IL-6 has attracted considerable attention, interleukin 11 (IL-11), another member of the IL-6 family, has long been overlooked, and little is known regarding its specific function in non-small cell lung cancer (NSCLC). In this study, we explored IL-11’s role in NSCLC and the detailed mechanism behind it. Methods: Cell proliferation in response to IL-11 was determined by colony formation, BrdU incorporation and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Cell motility was measured by Transwell and wound healing assays. NSCLC xenograft models were used to confirm oncogenic function of IL-11 in vivo. Immunohistochemical staining and western blot assay were performed to detect epithelial–mesenchymal transition (EMT) markers and cell signaling pathway alterations. Eighteen NSCLC patients and 5 normal lung samples were collected together with data from an online database to determine the link between IL-11 expression and malignant progression. Results: We observed that IL-11 was upregulated in NSCLC samples compared with normal tissue samples and correlated with poor prognosis. Data from in vitro and in vivo models indicated that IL-11 promotes cell proliferation and tumorigenesis. Cell migration and invasion were also enhanced by IL-11. Epithelial–mesenchymal transition (EMT) was also observed after IL-11 incubation. Furthermore, IL-11 activated AKT and STAT3 in our experimental models. In addition, we observed that hypoxia induced IL-11 expression in NSCLC cells. Deferoxamine (DFX) or dimethyloxalylglycine (DMOG) induced hypoxia-inducible factor 1-alpha (HIF1α) upregulation, which enhanced IL-11 expression in NSCLC cells. Conclusions: Taken together, our results indicate that IL-11 is an oncogene in NSCLC, and elucidating the mechanism behind it may provide insights for NSCLC treatment.

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“…HIFA is nuclear and constitutively expressed, whereas HIFB is cytoplasmic and controlled by oxygen-dependent enzymes. Several studies have indicated that HIF1A activity in various tumors is associated with poor prognosis through the regulation of angiogenesis, invasion, or metastasis [38][39][40]. In addition to HIF1A, HIF2A has been found to be strongly expressed in tumor-associated macrophages [41] and renal cell carcinoma [42], indicating the important roles of HIF1A and HIF2A in tumor progression.…”

Peer Review #2 of "Comprehensive analysis of lncRNA-associated competing endogenous RNA network in tongue squamous cell carcinoma (v0.2)"

“…Thus, we speculate that SFTA1P may act as an oncogene. Our ceRNA network indicated that SFTA1P up-regulated the expressions of IL-11 or HOXC8 by binding mir-211, and elevated IL-11 or HOXC8 contributes to development of cancer , such as breast cancer (Cai et al 2018;Li et al 2014) and non-small cell lung cancer (Liu et al 2018;Zhao et al 2018b).…”

miR‐495 and miR‐5688 are down‐regulated in non‐small cell lung cancer under hypoxia to maintain interleukin‐11 expression

“…The IL-11 concentration in cell culture supernatants was determined by a human IL-11 immunoassay ELISA kit (R&D Systems, Minnesota, MN, USA). The assay was performed as previously described [21]. Briefly, 100 µL of assay diluent and 100 µL of standard or sample per well were added to the microplate and incubated for 2 h. After washing 4 times with the washing buffer supplied by the kit, the microplate was incubated with 200 µL of IL-11 conjugate for 3 h. After another 4 washes, 200 µL of substrate solution was added and incubated for 30 min.…”

“…Previous studies have shown that IL-11 was abnormally expressed in many solid tumors and was related to the tumor microenvironment [20]. Furthermore, our previous research findings showed that IL-11 functioned as a prominent pro-tumorigenic cytokine in NSCLC by activating the signal transducer and activator of transcription 3 (STAT3) and AKT pathways [21]. Therefore, inhibiting IL-11 signaling might be a promising therapeutic strategy for the treatment of NSCLC.…”