Prostate-specific IL-6 transgene autonomously induce prostate neoplasm through amplifying inflammation in the prostate and peri-prostatic adipose tissue
- Gang Liu†1,
- Jinyu Zhang†2,
- Lewis Frey3,
- Xiao Gang2, 6,
- Kongming Wu4,
- Qian Liu4,
- Michael Lilly5 and
- Jennifer Wu1, 2, 7Email authorView ORCID ID profile
© The Author(s). 2017
Received: 10 September 2016
Accepted: 30 December 2016
Published: 11 January 2017
The causative role of the pro-inflammatory cytokine IL-6 in prostate cancer progression has been well established at molecular level. However, whether and how IL-6 may play a role in prostate cancer risk and development is not well defined. One limitation factor to acquiring this knowledge is the lack of appropriate animal models.
We generated a novel line of prostate-specific IL-6 transgenic mouse model. We compared the prostate pathology, tumorigenic signaling components, and prostate tumor microenvironment of the IL-6 transgenic mice with wild type littermates.
With this model, we demonstrate that IL-6 induces prostate neoplasm autonomously. We further demonstrate that transgenic expression of IL-6 in the prostate activates oncogenic pathways, induces autocrine IL-6 secretion and steadily-state of STAT3 activation in the prostate tissue, upregulates paracrine insulin-like growth factor (IGF) signaling axis, reprograms prostate oncogenic gene expression, and more intriguingly, amplifies inflammation in the prostate and peri-prostatic adipose tissue.
The pro-inflammatory IL-6 is autonomous oncogene for the prostate. IL-6 induces prostate oncogenesis through amplifying local inflammation. We also presented a valuable animal model to study inflammation and prostate cancer development.
Emerging evidence indicated that the pro-inflammatory cytokine IL-6 may play a causative role in prostate cancer progression . For instance, IL-6 has been shown to facilitate prostate cancer progression to androgen-independent disease and potentially to promote bone metastasis and neuroendocrine differentiation (NED) [2–7]. Elevation of serum levels of IL-6 or activation of IL-6 signaling pathways in the tumor tissue correlates with the shortened overall survival and time to progression in prostate cancer [8–13]. In vitro and xenograft in vivo studies have demonstrated that IL-6 plays a causative role to promote oncogene-immortalized non-tumorigenic prostate epithelial cells to overt malignancy . Conclusions from recent clinical studies propose that serum IL-6 can be a negative prognostic biomarker for prostate cancer .
IL-6, a multi-functional cytokine that can be produced by various cell types, including immune/inflammatory cells (monocytes, macrophages, B cells, T cells, nature killer cells), fibroblasts, keratinocytes, endothelial cells, and also tumor cells, plays a pivotal role in controlling cell differentiation and cancer cell survival [15, 16]. IL-6 signals through the adaptor molecule gp130 via canonical membrane bound IL-6R and/or alternatively soluble IL-6R trans-signaling in IL-6R-gp130+ cells to initiate the downstream activation cascade [17, 18]. It has been well established that activation of the signal transduction and activator of transcription 3 (STAT3), a key effector protein of IL-6 signaling, is critical in initiating oncogene transcription and cancer progression . IL-6 can promote tumorigenic conversion of oncogene-immortalized benign cells through STAT3-mediated trans-activating other cellular signaling pathways, such as MAPK, PI3K/AKT, and insulin-like growth factor I receptor (IGF-IR) signaling axis [14, 20]. Persistent activation of STAT3 in prostate carcinomas has been correlated with the shortened survival of cancer patients [8–12]. Upregulation of IL-6 and activation of STAT3 autocrine pathway have been shown to account for the major mechanisms of cancer cell resistance to therapy [19, 21, 22]. Based on these understandings, recent studies have been focused on targeting IL-6 or IL-6 signaling pathways in cancer patients [19, 23–25].
Although the significance of IL-6 in prostate cancer progression is well established, whether IL-6 plays a causative role in prostate cancer risk and early development is not clearly well defined. Polymorphisms of IL-6 gene have been associated with prostate cancer risk [26–28]; however, bona fida evidence of IL-6 as a sole factor in prostate cancer risk is lacking. Most of pro-tumorigenic evidence of IL-6 in prostate cancer was achieved from experiments of oncogene-immortalized cell lines or clinical correlation studies. To address the fundamental biological question whether IL-6, as the major pro-inflammatory cytokine, can initiate prostate tumorigenesis in an autologous state, here, we developed a prostate-specific IL-6 transgenic mouse line in which IL-6 was directed to express specifically in the prostate by the rat probasin promoter. With this model, we demonstrated that overexpression of IL-6 alone was sufficient to induce prostate epithelium malignant neoplasm. We demonstrated that enforced expression of IL-6 in the prostate activated STAT3 pathway in the epithelium and stroma, induced an IL-6 autocrine and insulin-like growth factor (IGF) paracrine loop, reprogrammed prostate oncogenic gene expression, and amplified pro-tumorigenic inflammation in the prostate tissue microenvironment and peri-prostatic adipose tissue. Our study suggests that IL-6 is an unconventional “oncogene” for the prostate. Moreover, our prostate-specific IL-6 transgenic mouse can serve as a valuable model to study inflammation-associated prostate cancer prevention.
IL-6 transgene induces early prostate neoplastic transformation
Summary of the prostate pathology of pbIl-6 mice and wild type littermate surveyed at various ages
In our previous report, we described multiple effects of IL-6 on immortalized benign human prostate epithelial cells . Consistent with these findings, the prostate epithelium of the transgenic pbIL-6 mice demonstrated a focally dramatic decrease of membranous expression of E-cadherin (Fig. 2a, b). The loss of E-cadherin signifies a reduction in cell-cell adhesion and a shift of the prostate luminal cells from a clearly differentiated epithelial to a more mesenchymal phenotype and also an early stage of transformation [33, 34]. The disrupted expression of basal cell marker p63 in the prostate gland from the pbIL-6 mice also signifies the early transformation events of the prostate [35, 36] (Fig. 2a). Consistent with our previous report of the tumorigenic potential of IL-6 in epithelial cell lines , the prostate epithelium from pbIL-6 mice had a significant higher index of Ki-67 positivity (Fig. 2a), suggesting an active proliferation state. Moreover, in comparison to WT littermate, not only a markedly overall elevation of the oncogene β-catenin but also more significantly elevated accumulation of β-catenin in the nucleus was presented in the prostate epithelium of the pbIL-6 mice (Fig. 2a, e). Furthermore, in comparison to the B6 WT littermates, androgen receptor (AR) was not only significantly increased in the levels of expression in the prostate epithelium of the pbIL-6 mice, but also predominantly translocated to the nucleus (Fig. 2a, f), an indication of increased AR activity. Given that IL-6 has been known to increase AR activity in castration-resistant prostate cancer , together, these molecule features of the prostate epithelium of the pbIL-6 mice endowed its neoplasia features and tumorigenic properties, which were further substantiated by elevated expression of oncogenes, such as c-Fos and k-Ras as measured by quantitative RT-PCR (Fig. 2c, d).
IL-6 transgene activates autocrine IL-6 loop and upregulates the IGF-I signaling axis in the prostate
We and the others have previously described that IL-6 signaling trans-activates the endocrine IGF signaling axis in cancer cells . Activation of IGF signaling axis has been shown to play an essential role in tumor cell survival and proliferation . In pbIL-6 mice, a significantly increased expression IGF-I and IGF-II was demonstrated by quantitative RT-PCR (Fig. 3c, d). Collectively, these data suggest that trans-activating IGF signaling axis may also contribute to IL-6-induced epithelium transformation.
IL-6 transgene universally activates STAT3 pathway and reprograms gene expression in the prostate tissue
We further addressed how expression of IL-6 in the prostate may impact prostate gene expression profiles using Affymetrix whole-transcript RNA array analyses. One hundred thirty genes were identified at least 2-fold upregulated in the prostate of pbIL-6 mice in comparison to the WT littermates at the significant level of P < 0.05. The most significantly regulated genes are indicated in the volcano plot of Fig. 4b and Additional file 1: Tables S1–S4. Notably, a large portion of these upregulated genes are associated with inflammation, oncogenesis, or metabolism. The most relevant upregulated genes, such as cytokine IL-6 and oncogenes c-JUN, β-catenin, and Ras have been validated by quantitative RT-PCR (Figs. 2c–e and 3a). IGF-I and the androgen signaling downstream gene TMPRSS2 were also shown in the gene expression array to be upregulated (Additional file 1: Table S3). Many of these transcriptional changes are consistent with our previous findings with in vitro IL-6 overexpression studies . Together, these data indicate that expression IL-6 not only intrinsically reprograms the prostate to express pro-tumorigenic genes but also primes a pro-inflammatory tissue microenvironment whereby the combinatory effect may contribute to prostate neoplasm.
IL-6 amplifies pro-tumorigenic inflammation in prostate tissue microenvironment
Emerging evidence suggests that chronic or recurrent inflammation may initiate and promote cancer development, including prostate cancer [40–43]. This process involves multiple inflammatory cells as well as a broad array of inflammatory cytokines . IL-6, as a major pro-inflammatory cytokine can be secreted by an array of inflammatory cell types, are not only the growth factor for epithelial cell, but also critical for the survival and proliferation of inflammatory cell types in the tissue microenvironment. This process is frequently referred as “smoldering” inflammation [40, 44–46].
The link between IL-6 and prostate cancer progression has been well established . However, whether IL-6 alone can induce de novo prostate tumor initiation in an autologous state is unknown. Using the novel prostate-specific IL-6 transgenic mice, we clearly demonstrate the oncogenic property of IL-6. We show that elevated expression of IL-6 alone in the prostate is sufficient to induce local neoplasm. We further show that constitutive IL-6 expression in the prostate, resembling chronic inflammation, activates STAT3, reprograms prostate gene transcription to pro-tumorigenic, activates the autocrine IL-6 and paracrine IGF signaling axis, and amplifies inflammation in the prostate and peri-prostatic adipose tissue. This is the first study, to our knowledge, that established a direct link between IL-6 and de novo tumorigenesis in the prostate. Our data conclude that IL-6 is an “unconventional” oncogene in prostate tumorigenesis.
Given that IL-6 is a common cytokine produced by many inflammatory cell types, our study also suggests a direct link between inflammation and carcinogenesis. The link between inflammation and cancer has been suggested since centuries ago by Dr. Rudolf Virchow . However, the conventional wisdom considered inflammatory acts as a “stimuli” to other genotoxic events to facilitate cancer development. Our current study clearly demonstrated that inflammation can also act as an “ignitor” to autonomously initiate de novo tumor development without other genomic insults, in which context the pro-inflammatory cytokine IL-6 serves as a critical mediator or “lynchpin” .
Elevation in IL-6 expression and loss of E-cadherin have been linked with increase cancer stem cell population in various cancer types [55–57]. In this study, we did not observe positivity for cancer stem cells with markers such as CD133, OCT4, or Nanog (data not shown), suggesting that rising or re-populating of cancer stem cells is not the major mechanism by which IL-6 induces prostate tumorigenesis in current model.
Prostate cancer is a heterogeneous neoplasm which is regulated by factors, such as age, hormones, obesity, and dietary habits, in addition to genomic insults common to other cancers. Many epigenetic and clinical follow-up studies have suggested a strong link between chronic inflammation and prostate cancer risk [43, 58–60]. However, to date, our understandings are limited by lacking appropriate animal models to study the development of prostate cancer from chronic inflammation. In the current study, we not only demonstrated that IL-6 is an oncogene for prostate cancer, but also present a valuable model that recapitulates the role of inflammation in prostate cancer development.
Generation of transgenic mice
Mice were bred and housed under specific pathogen-free conditions in the University of Washington animal facility in accordance with the institutional guidelines. All mice used in this study were on the C57BL/6 (B6) background. The rPB-IL6 expression cassette was constructed by replacing the SV40T human IL-6. The entire rPB-IL6 expression cassette was gel isolated following digestion with Hind III and was microinjected into fertilized B6 embryos at University of Washington Comparative Medicine transgenic core facility. Transgenic progeny were identified by PCR analysis of DNA extracted from tail biopsies using the forward primer specific for rPB (5′-acaagtgcatttagcctctccagta-3′) and the reverse primer specific for IL-6 (5′-tgtgtcttggtcttcatggc-3′). All experimental mice were randomly assigned to cohorts and euthanized at indicated age for evaluation of GU and the prostate.
Total RNA was extracted using TRizol (Invitrogen) followed by treatment with DNAase I (Fermentas) to exclude the genomic DNA before reversal transcription. Complementary DNA (cDNA) was synthesized using the SuperScript II kit (Invitrogen). A volume of 1 μL of cDNA was mixed with Power SYBR Green PCR MasterMix (Applied Biosystem, Carlsbad, CA, USA), and specific primer sets were added to a final concentration of 400 nM in 20 μl of reaction mixture. The reaction was performed on an ABI9700 Machine. Data were analyzed using the Lightcycler software v3.5 (Roche Applied Science, Indianapolis, IN, USA). Each sample was assayed in triplicates. Target mRNA levels were normalized against mouse GAPDH. The primers used are listed in Additional file 1: Table S5.
Total RNA of the prostates from four 24-week-old pbIL-6 transgenic male mice and wild type C57BL/6 littermates was obtained as described above. After RNA quality confirmation with a Bioanalyzer (Agilent), 300 ng of each RNA sample was used in the Affymetrix Whole-Transcript Sense Target Labeling Assay (Rev 3), followed by hybridization to a GeneChip Mouse Gene 1.0 ST Array. Eight GeneChips were used to provide biological replicates of each genotype. The Affymetrix Expression Console (v 1.1) was used to normalize data and determine signal intensity (RMA-Sketch). Analysis was performed using DAVID Bioinformatic software and R2 statistical software with bonferroni correction.
Histological and immunohistochemical examination
The mouse prostate tissues were fixed in 10% formaldehyde and embedded in paraffin wax. Five-micrometer sections were cut and stained with H&E for pathological evaluation. Sections were also stained with antibodies specific for: (1) E-cadherin (Santa Cruz); (2) p63 (Thermo Scientific); (3) Ki67 (Thermo Scientific); (4) β-catenin antibody (AbCAM); (5) AR (Santa Cruz); (6) pSTAT3 (Cell signaling); (7) macrophage (F4/80 or Mac-2; eBioscience); (8) B cells (B220, eBioscience); and (9) anti-CD3 (Thermo Scientific). The staining procedure has been previously described . Briefly, sections were deparaffinized and incubated for 10 min in 10 mM citrate buffer (pH 6.0) at 95 °C for antigen retrieval. Endogenous peroxidase activity was quenched with 3% hydrogen peroxide in methanol. After quenching endogenous peroxidase activity and blocking nonspecific binding, slides were incubated with specific primary antibody overnight at 4 °C followed by subsequent incubation with the appropriate biotinylated secondary antibody provided with Vectastain Elite ABC Kit. Color was developed with DAB as the perioxidase substract. All slides were counterstained with hematoxylin and mounted with Permount. Ten randomly selected fields of IHC-stained sections of the prostates from individual mice were counted for the positively stained cells and used for statistical analysis.
All results are expressed as the mean ± SEM. Differences between the mean of groups were analyzed using student’s t test with one-way ANOVA analyses. In most cases, P < 0.05 was considered as significant.
We thank the University of Washington Transgenic Core Facility for generating the founder line of the transgenic mice. We acknowledge John Jarzen for the technical support for some part of the immunohistochemistry staining.
This work was supported by NIH-NCI grant 1R01CA149405, R01 CA204021, and A. David Mazzone-Prostate Cancer Foundation Challenge Award (to J.Wu).
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its Additional file 1.
JW conceived the concept and prepared the manuscript. GL generated the transgenic construct and characterized the pathology of transgenic mice. JZ further performed the characterization of inflammatory pathways. GX performed part of the β-catenin staining. LF performed the cDNA array data analyses. QL, KW, and ML provided valuable discussion in the interpretation of the experiment data. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
All animal studies are approved by IACUC at the Medical University of South Carolina, the approval number is AR3077.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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