AJBM Volume 1, Issue 1, pages 4–6, November 2013 Full-Text PDF
Salam Alhasani*1 and Nasser Ghaly Yousif 2
Interleukin 23 (IL-23) belongs to interleukin 6 super-family . IL-12/23 p40 is the common subunit for them, which is covalently linked to either a p19 subunit to form IL-23 or a p35 subunit to form IL-12 . Both cytokines are mainly expressed by activating dendrite cells or macrophages under the stimulation of pathogens. IL-23 was also reported to be secreted by tumor associated macrophages in tumor microenvironment .
Interestingly, IL-23 spur different immune pathways . IL-12 induces IFN-γ-producing Th1 cell development and enhances cytotoxic, anti-microbial and anti-tumor responses; whereas IL-23 expands Th17 cells, which is mainly involved in the pathology of autoimmunity and chronic inflammatory disease .
Although the role of Th17 in tumor progression remains controversial, the role of IL-23 in tumor incidence and metastasis was established in the mouse model. For example, mice lacking IL-23p19 were resistant to DMBA/TPA-induced skin papilloma [6-7]. Recently, IL-23 was also reported to promote carcinogenesis and metastasis in the 3′-methylcholanthrene induced fibrosarcoma through suppressing the innate immune response . However, the role of IL-23 in metastatic prostate cancer is unclear. In this study, we found that IL-23 was highly expressed in metastatic prostate cancer cells. We further proved that IL-23 could directly promote prostate cancer metastasis via a STAT3/ROR gamma signal, so we further explored the relationship between IL-23 and STAT3/ROR gamma in prostate metastasis. We found that IL-23 and STAT3/ROR gamma were highly correlated in metastatic prostate cancer cell lines directed.
STAT3 belongs to the signal transducer and activator of transcription (STAT) family of signal responsive transcription factors, which consists of seven members encoded by distinct genes. In non-stimulated cells, STAT3, like other STATs proteins, are kept in an inactive cytoplasmic form. Then, once activated, STAT3 translocate into the nucleus where it behaves as a transcription activator for a broad array of targeted genes. Typically, STAT3 activation is induced by phosphorylation on a critical tyrosine residue (Tyr 705) that triggers STAT3 dimerization thanks to reciprocal phosphotyrosine-SH2 domain interactions. Even if multiple tyrosine kinases have been described as intracellular activators of STAT3 activity (such as EGFR, Src, ERK), the phosphorylation of STAT3 on tyrosine 705 is mainly regulated by members of Janus-activated kinases with JAK1 as key modulator . In addition to tyrosine 705 phosphorylation, STAT3 is also activated through serine (Ser 727) phosphorylation. This phosphorylation is commonly regulated by protein kinase C, mitogen-activated protein kinases, and CDK5.
It is now well established that STAT3 signaling is a major intrinsic pathway driving apoptosis, inflammation, cellular transformation, survival, proliferation, invasion, angiogenesis and metastasis of cancer [10-11]. However, compelling evidence has now shown that STAT3 is constitutively activated in many human cancers . Indeed, many receptor-signaling pathways are. Many regulated genes induced by STAT3 in turn activate the same STAT3 pathways and keep a stable feed forward loop going between tumor cells and tumor-interacting immune cells. In addition, the own tumorigenic properties of STAT3 highlight its oncoprotein status by driving malignant properties related to chronic inflammation .
Thereby, this explains that STAT3 has been characterized as a central actor for inflammation-induced cancer. STAT3 activation occurs in both cancer and stromal cells thereby allowing a crosstalk between these two cellular types. This activation is rapid and transient under normal biological conditions and mediated by a large number of extracellular stimuli including cytokines (IL-6, IL-10, IFNs, TNF-α) and growth factors.
This review investigated, for the first time, the role of IL-23 in prostatic cancer patients showing a significant increase respect the control group. However, further validations are needed in larger studies to better investigate the implications of IL-23 increase in these patients.
1. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13: 715–725.
2. Kortylewski M, Xin H, Kujawski M, Lee H, Liu Y. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell 2009;15:114–123.
3. Langrish CL, McKenzie BS, Wilson NJ, de Waal Malefyt R, Kastelein RA. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev 2009; 202: 96–105.
4. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201: 233–240.
5. Nasser ghaly yousif. Fibronectin promotes migration and invasion of ovarian cancer cells through up-regulation of FAK-PI3K/Akt pathway. Cell Biol Int 2013 Sep 21. doi: 10.1002/cbin.10184.
6. Teng MW, Andrews DM, McLaughlin N, von Scheidt B, Ngiow SF. IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis. Proc Natl Acad Sci USA 2010; 107: 8328–8333.
7. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signaling and immune regulation. Nat Rev Immunol 2007; 7: 454–65.
8. Hirano T, Ishihara K, Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 2000; 19: 2548–56.
9. Bromberg J, Darnell JE., Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 2000; 19: 2468–73.
10.Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798–809
11.Yousif NG, Al-Amran F, Hadi N, Lee Jillen, and Adrienne J. Expression of IL-32 modulates NF-κB and p38 MAP kinase pathways in human esophageal cancer. Cytokine 2013; 61(1): 223-7.
12. Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009; 15: 91–102.
13. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009; 15: 103–13.