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IL-22 is related to development of human colon cancer by activation of STAT3
© Jiang et al.; licensee BioMed Central Ltd. 2013
Received: 20 September 2012
Accepted: 30 January 2013
Published: 5 February 2013
It has been previously reported that IL-22, one of the cytokines secreted by Th17 cells, demonstrates both a protective and inflammatory promotion effect in inflammatory bowel disease (IBD) through STAT3 signaling activation. We sought to investigate the role of IL-22 expression in colon cancer (CC).
The expression of IL-22 and related molecules were detected in human CC, the detail function and mechanism of IL-22 were investigated by in vivo and in vitro model.
Our results demonstrated significant upregulation of IL-22 in human CC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, our findings demonstrated that IL-22 expression was significantly higher in ulcerative colitis (UC) tissues versus normal colon tissues. Both IL-22 receptor α1 (IL-22RA1) and IL-23 were highly expressed in CC and UC tissues compared to normal controls. TILs exhibiting various IL-22 expression levels isolated from CC patients were demonstrated to enhance tumor growth and metastasis co-transplanted with Hct-116 cells underwent subcutaneous transplantation in mice model. Tumor growth and metastasis was promoted by STAT3 phosphorylation and upregulation of its downstream genes such as Bcl-xl, CyclinD1, and VEGF. In vitro studies confirmed the anti-apoptotic and pro-proliferation effect of IL-22 according to the BrdU cooperation assay and peroxide induced apoptosis analysis with or without the presence of IL-22.
In this study we demonstrated that excessive IL-22 in the CC and UC microenvironment leads to tumor growth, inhibition of apoptosis, and promotion of metastasis depend on STAT3 activation.
Colon cancer (CC) is a common and lethal cancer that exhibits regional variation in incidence and mortality around the world. Globally, CC is the third most commonly diagnosed cancer in males and the second in females, with over 1.2 million new cases and 608,700 deaths every year . Ulcerative colitis (UC) is one of the risk factors for CC. In 1988 it was reported that sustained UC over a period of 8–10 years significantly increases the risk of CC by 0.5–1% . Furthermore, after 40 years of UC, approximately 25–30% of patients will have developed CC . Both UC and CC exhibit a strong link with an inflammatory microenvironment composed of a large population of normal and premalignant intestinal epithelial cells (IECs) or tumor cells, immune cells, macrophages etc.; the determinants of the pro- or anti-tumor effect within the microenvironment have become central in cancer research .
Moreover, much of the growth that stimulates the cross-talk between immune and IECs or malignant cells is mediated by cytokines that activate the oncogenic transcription factor STAT3 , a major intrinsic activator in cancer inflammation and a regulator of the tumor microenvironment [6, 7]. STAT3 induces the expression of genes important for cell cycle progression (such as cyclinD1 and PCNA) as well as suppression of apoptosis (Bcl-XL, Bcl-2, and Mcl-1), eventually promoting cell survival and proliferation during colitis-associated tumorigenesis [7–9]. It has been previously demonstrated that specific ablation of STAT3 in intestinal epithelial cells suppresses cell proliferation and reduces tumor incidence in both a DSS-induced colitis model and colitis associated cancer (CAC) model [10, 11]. Furthermore, enhanced STAT3 activation has been shown to exhibit an accelerating effect on CAC development by mutation of the gp130 receptor .
The most famous STAT3 activator, IL-6, is widely recognized to play an inflammation-related role in colon cancer. In recent years, the involvement of IL-6 in UC and CC has been an area of active investigation in both experimental animal models and clinical research [12–15]. Within the microenvironment of CC or UC, IL-6 originates from various cells including IECs and immunocytes, such as Th17 cells. Th17 cells represent a novel subset of T helper cells that exhibit high expression of RORγT and secrete cytokines, including IL-17A, IL-17 F, IL-21, and IL-22 [9, 16–19]. Naïve T cells can be recruited and differentiate into Th17 cells that are polarized by IL-23 in concert with IL-1β, IL-6, IL-23, TNF-α, and TGF-β, which is abundant in both UC and CC [20–23]. The role played by Th17 cells in tumor pathogenesis is controversial and remains unclear. On the one hand, IL-17 has been demonstrated to be a valuable marker associated with poor prognosis that promotes angiogenesis via stimulation of VEGF production of cancer cells in CC [24, 25]. Abundant Foxp3+/IL-17+ T cells have been detected in CC tissues that exhibited the capacity to drive cancer initiation in cells with high levels of phosphorylated Akt and MAPK . On the other hand, endogenous IL-17 has been shown to reduce tumor growth and lung metastasis due to the effects of IFNγ + NK and IFNγ + tumor-specific T cells; these results suggest that IL-17 potentially promotes protective tumor immunity . Therefore, further investigation concerning the role of Th17 cells in CC is warranted.
As one of the cytokines secreted by Th17 cells, the majority of CC related cytokine studies have reported that IL-22 is not centrally involved. However, IL-22 was demonstrated to exhibit general intestinal antimicrobial defense, regeneration, and protection against injury in a series of studies by Wolk et al. . Recently, the rs1179251 SNP in IL-22 was demonstrated to be associated with risk of colon cancer ; Nagakawa et al. demonstrated that IL-22 does not directly act on immunocompetent cells, and artificially IL-22 expression in CC cell line can favor apothanasia of inoculated hosts ; An additional two studies were conducted to investigate the role of IL-22 in UC that revealed that IL-22 played a pivotal role in UC pathophysiology through both DMBT1 and REGα [31, 32]. However, the specific role of IL-22 in CC remains unclear. Therefore, we sought to investigate IL-22 expression and the related molecules in human CC in order to further elucidate whether IL-22 acts as a tumor promoter and to investigate the underlying mechanisms of action.
Clinical characteristics of the 82 colon cancer patients
No. of patients
Age, year (median, range)
Histological grade (WHO)
Isolation and culture of human CC infiltrated leukocytes
The fresh tumor tissues samples were collected from 82 cases of histologically confirmed colon cancer obtained from hospitalized cancer patients who underwent surgery. The tumor pieces were washed twice in RPMI 1640 (Invitrogen, CA). The fatty, connective, and/or necrotic tissues were removed from the tumor mass in a 10 cm dish. Next, the tissue was cut into 1–2 mm pieces in RPMI 1640, and the minced tumor pieces were transferred into a 15-ml or a 50-ml conical tube and incubated with a triple enzyme digestion medium that contained DNase (30 U/ml), hyaluronidase (0.1 mg/ml), and collagenase (1 mg/ml) for 2 hours at room temperature with gentle shaking. The samples were then resuspended in 10 ml RPMI 1640, filtered through a 70-μm cell strainer (BD), placed into several wells containing 1 ml of T-cell growth medium (RPMI 1640 with 10% human AB serum, supplemented with 5 U/ml human rIL-2) in a 24-well plate, the TILs was processed immediately for IL-22 detection by flow cytometry. To obtain IL-22(+)TILs, lymphocytes were isolated by flow cytometry, and maintained in T-cell growth medium. A polarization stimulation to Th22 cells was performed according Th22 condition described as previous report  which can be briefly described as 50 ng/ml TNF-α, 20 ng/ml IL-6, 5 μg/ml anti–IL-12, and 5 μg/ml anti–IL-4 for 5 days, further mixed with Macrophage and NK cells isolated from TILs. We nominated this cell mixture as IL-22 (+) TILs, and preparing for in vitro and in vivo assays.
In vivo tumorigenesis assay
All animal experiments were performed in accordance with the guidelines of the Animal Care Committee, Nanjing Medical University. Immunodeficient nude mice (5–6 weeks of age) were purchased from Charles River Laboratories, China. All operation concerning animal was performed according to ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. Three groups, with 5 mice each, were injected subcutaneously with three cell mixtures respectively: Hct-116 cells alone, and Hct-116 cells plus TILs obtained from each of two CC patients (ratio 1000:1), respectively, at cell density of 3 × 106 cells in 300 μl saline solution. Animals were sacrificed 6 weeks after transplantation, and the animals were monitored regularly for tumor occurrence throughout the entire experiment period.
Quantitative real-time PCR
Reverse transcription reactions were performed using the SuperScript First-Strand Synthesis System (Invitrogen, CA), and the RNA templates were treated with DNase to avoid genomic DNA contamination. To determine the relative level of cDNA in the reverse transcribed samples, real-time PCR analyses were performed using an Applied Biosystems 7300 Detection System (Applied Biosystems, CA). The primers sequence were Forward Primer: GCTTGACAAGTCCAACTTCCA, Reverse Primer: GCTCACTCATACTGACTCCGTG, with 140 bp amplification length for human IL-22, and Forward Primer: AAGGTGAAGGTCGGAGTCAAC, Reverse Primer: GGGGTCATTGATGGCAACAATA, with 102 bp amplification length for human GAPDH. The primers were synthesized by Genscript Inc. (Nanjing, China). Real-time PCR reactions were performed in accordance with the instructions of the SYBR® Premix Ex Taq™ kit. (Takara, Japan). Data were normalized with the GAPDH levels in the samples.
Proteins were extracted from cell and mouse tissues and quantified using a protein assay (Bio-Rad Laboratories, CA). Protein samples (30 μg) were fractionated by SDS-PAGE and transferred to a nitrocellulose membrane. Immunoblotting was conducted using antibodies against IL-22, IL-22RA1, total STAT3, p-STAT3(S727), Bcl-xl, CyclinD1, and VEGF (all purchased from Abcam Inc, MA). The results were visualized via a chemiluminescent detection system (Pierce ECL Substrate Western blot detection system, Thermo Scientific, IL) and exposure to autoradiography film (Kodak XAR film).
All the tissues were removed and fixed in 4% paraformaldehyde overnight at 4°C, processed, and sectioned at 5 μm thickness. The sectioned slides were stained immunohistochemically for IL-22, IL-22RA1, IL-23, CEA, and p-Stat3 (S727) (all purchased from Abcam Inc., MA) using techniques described previously .
The peripheral lymphocytes and TILs were stimulated at 37°C for 5 hours with Leukocyte Activation Cocktail (BD Pharmingen). Thereafter, cells were stained with surface markers, fixed and permeabilized with IntraPre Reagent (Beckman Coulter), and finally stained with intracellular markers. Data were acquired on FACSVantage SE and analyzed with CellQuest software. The fluorochrome-conjugated mAbs against CD3, CD4, CD8, CD14, CD16, and CD56 are purchased from BD Pharmingen (CA).
BrdU cooperation and immunofluorescense assay
Hct-116, Hct-116 + TILs, Hct-116 + IL-22(+)TILs, Hct-116 + IL-22(+)TILs + IL-22mAb, Hct-116 + IL-22(+)TILs + IL-6mAb (antibodies was all purchased from Abcam Inc., MA. 10 μg/ml anti-IL-22 or anti-IL-6 3 hours prior to the assay) and Hct-116 + IL-22(+)TILs + WP1066 (EMD Chemical USA, MA, 5uM for the concentration of WP1066) were cultured on coverslips such that they were rapidly dividing. Cells were incubated with 100 μM BrdU for 2 hours, the medium aspirated, and immediately fixed and permeabilized in cold methanol:acetone (1:1), then blocked with PBS/3% BSA (Sigma-Aldrich, MO), and incubated with primary BrdU monoclonal antibody (Sigma-Aldrich) diluted in 3% BSA/PBST (0.2% Triton X-100). Following incubation with rabbit anti-mouse FITC-conjugated secondary antibody (Sigma-Aldrich), slides were mounted in Mounting Medium (with 1.5 μg/ml DAPI) (Santa Cruz), and visualized with a fluorescense microscope (Axiovert 200; Zeiss, Stuttgart, Germany).
Peroxide induced apoptosis and flow cytometry analysis
Hct-116, Hct-116 + TILs, Hct-116 + IL-22(+)TILs, Hct-116 + IL-22(+)TILs + IL-22mAb, Hct-116 + IL-22(+)TILs + IL-6mAb and Hct-116 + IL-22(+)TILs + WP1066 (same treatment to BrdU cooperation assay) were cultured with complete medium with 0.5 mM peroxide overnight. Next, the cells were harvested and fixed with 70% cold EtOH at −20°c overnight, then further analyzed by flow cytometry (FACSCaliburTM; BD Biosciences, NJ) using a PI/Annexin staining kit (Invitrogen, CA).
The results are expressed as mean ± SD. Comparisons between two groups were performed using the student’s t-test or the Mann–Whitney U test, as appropriate. All statistical analyses were performed using SPSS statistical software (version 13.0), and two-tailed t-tests were applied to all data unless otherwise specified, with P < 0.05 considered to represent a statistically significant result.
Excessive IL-22 in tissues of colon cancer and ulcerative colitis
IL-22 related proteins are also over-expressed in human colon cancer and ulcerative colitis
IL-22 is related to promoted tumor growth and metastasis in vivo
We investigated metastasis by analyzing the lymph nodes that emerged around the tumor tissue (2/6 in the TILs1 group and 4/6 in the TILs2). We confirmed that Hct-116 invaded the lymph nodes with IHC staining for carcino-embryonic antigen (CEA), which is negative in normal lymph nodes (Figure 4E). No visceral metastasis was found in all groups. Based on this result, we analyzed VEGF expression in the tumor tissues, and our findings indicated that VEGF expression was elevated in correlation with TILs (Figure 4D); increased VEGF expression is also a downstream target of STAT3 activation.
IL-22 enhances tumor proliferation and anti-apoptotic ability by activating STAT3 signaling in vitro
It has been previously demonstrated that IL-22 plays a protective role within many organs, such as anti-microbial defense, regeneration, and protection against injury [36, 37]. These findings are based on the distribution of two reporters: IL-22R1 (IL-22RA1) and IL-10R2. IL-22R1 is located primarily in the skin, digestive tract (including pancreas and liver), lung, and kidney, while IL-10R2 is ubiquitously expressed [28, 36]. IL-22 acts as a protector in intestinal mucosal healing through multiple signaling activation steps. In an intestinal infection with C. rodentium, IL-22 is produced earlier than IL-17A and it plays a decisive role, whereas IL-17A does not . Moreover, Sugimoto et al. demonstrated that IL-22 contributes to rapid amelioration of local inflammation associated with Th2-mediated colitis . Additionally, studies in genetically engineered mice have demonstrated that epithelial STAT3 activation in dextran sodium sulfate colitis is dependent upon IL-22 rather than IL-6, and that both IL-22 and epithelial STAT3 is important in wound-healing experiments in vivo . Therefore, according to these studies, most of the protective roles of IL-22 in the intestinal tract are linked to STAT3 in IECs, a pleiotropic transcription factor with important functionality in cytokine signaling in a variety of tissues [41, 42]. However, IL-22 has also been considered an inflammatory driver in IBD based upon both clinical evidence and mouse model data. Highly elevated serum levels and a potential systemic role for IL-22 have been demonstrated to correlate with disease severity in patients with Crohn’s disease (CD). In 2005 it was shown that IL-22 was much higher in UC compared to CD, and a study of human IBD revealed that IL-22 derived from activated T cells acts on human colonic subepithelial myofibroblasts to stimulate secretion of proinflammatory cytokines and matrix-degrading molecules, thus demonstrating its proinflammatory/remodeling role in IBD . Similar outcomes have been obtained from a colitis mouse model, indicating that highly elevated IL-22 expression was an inflammation driver in either a direct or indirect manner [39, 43]. More recently, the role of IL-22 in mouse IBD and colon cancer have been clarified by Huber et al. which indicated that the ratio of IL-22/IL-22BP is critical in regulating intestinal tissue repair and tumorigenesis in the colon .
As discussed above, STAT3 activation by IL-22 plays both protective and inflammatory driver roles in human IBD, which is similar to what occurs in the liver. IL-22 demonstrates a directly protective role in acute liver injury, which has been demonstrated by both the Radaeva and Zenewicz research groups. However, the authors also hypothesized that the protective effect of IL-22 was due to activation of STAT3, and that its anti-apoptotic and regeneration promoting effect potentially contributes to the development of HCCs [45, 46]. This hypothesis was verified by both us and Park et al. recently, and it has been revealed that IL-22 exhibits opposing short-term and long-term effects in the liver which in turn promote cell proliferation, survival, metastasis, and transformation from chronic hepatitis to HCC [34, 47]. Therefore, we investigated whether the opposing effects of short-term and long-term IL-22 activated STAT3 exist in the human intestinal tract. Initially, our investigation confirmed that massive levels of IL-22 were present in the UC tissues of the Chinese population. Secondly, we reported for the first time that excessive IL-22 also was present in human colon cancer. Furthermore, up-regulation of IL-22 in TILs derived from human CC was associated with the activation of STAT3 and exhibited tumor promotion and enhancement of metastasis in both in vitro and in vivo model.
The tumor microenvironment is composed of tumor cells, macrophages, and immunocytes etc. where the interactions between these cells involves their secreted cytokines and consists of a free-forward loop with persistent activation of STAT3 enabling promotion of tumor growth . Consistent with IL-23 and IL-22RA1, an IL-22 feed-forward loop in the CC or UC microenvironment has been demonstrated through our research. The IL-22 signal can be transmitted through a heterodimeric receptor complex that consists of IL-22R1 (IL-22RA1) and IL-10R2 [48, 49]. Unlike the ubiquitously expressed IL-10R2 chain, the IL-22RA1 chain was normally restricted to non-immune cells such as epithelial cells and hepatocytes . In correlation with overexpression of IL-22 in TILs of CC, IL-22RA1 is also overexpressed in colon cancer cells and in IECs of UC, which ensures the transmission of the IL-22 signal. Pro-tumor cytokine IL-23, which is also regulated by STAT3 [51, 52], is over expressed in CC and UC. Excessive expression of IL-23 plus TNF-α, IL-6, and IL-1β, which have already been demonstrated to be overexpressed in human CC, composed a milieu for infiltrated naive lymphocytes which were also enrolled by STAT3 activation to differentiate to Th17 cells expressing IL-22 [20–23]. In this study, we transplanted this IL-22 related tumor microenvironment beneath the skin of nude mice. The proliferation and metastasis enhancing effects of this free-forward loop were confirmed, and proliferation associated cyclinD1, cell survival associated BCL-XL, and metastasis associated VEGF were all upregulated and mediated by STAT3 activation, which was demonstrated by phosphorylation of S727 residue [9, 52]. Furthermore, these tumor growth and metastasis promotional effects of IL-22 were demonstrated to occur in a dose-dependent manner when various tumor microenvironments were transplanted with a range of IL-22 levels. We investigated more precise and accurate mechanisms with in vitro studies utilizing the IL-22 and IL-6 depletion assay; cell survival and tumor promotion was eliminated when IL-22 was blocked based upon the attenuated activation of STAT3 which is similar to IL-6, Moreover, the specialty of IL-22 effect through STAT3 signaling was verified by using STAT3 inhibitor WP1066.
This study revealed a previously unknown role of IL-22 in human UC and CC, which potentially enhances proliferation, cell survival, and metastasis. Further studies are warranted to investigate the potential of anti-IL-22 therapeutics for the prevention and treatment of human UC and CC.
This work was supported by grants from the National Natural Science Foundation (81072029, 91029721 and 81225017 to B.S.), the National Basic Research Program of China (2012CB910800 to B.S.). National Natural Science Foundation (81201528 to R.J.), the New Century Excellent Talents in University, Ministry of Education (NCET-09-0160 to B.S.). This work also supported in part by the program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU, and the Priority Academic Program of Jiangsu Higher Education Institutions. The authors declared no conflicts of interest.
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