|Year : 2016 | Volume
| Issue : 2 | Page : 48-54
Targeting Signal Transducer and Activator of Transcription 3 for Colorectal Cancer Prevention and Treatment with Natural Products
Weidong Li1, Cihui Chen2, Zheng Liu3, Baojin Hua4
1 Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing; Department of Infectious Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
2 Department of Oncology, Zhejiang Provincial Hospital of TCM, Hangzhou, Zhejiang, China
3 Department of Infectious Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
4 Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
|Date of Submission||03-Jan-2016|
|Date of Acceptance||07-Mar-2016|
|Date of Web Publication||29-Apr-2016|
Dr. Baojin Hua
Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 Beixiange, Xicheng District, Beijing 100053
Source of Support: None, Conflict of Interest: None
Signal transducers and activators of transcription 3 (STAT3), a transcription factor, plays key role in regulating the signal transduction events mediated by cytokines and growth factors. STAT3 is involved in many activities including survival, proliferation, differentiation, and apoptosis. Persistent activation of STAT3 has been demonstrated to be closely correlated to tumor cell proliferation, apoptosis, invasion, metastasis, and angiogenesis. Recent studies indicate that treatment with STAT3 inhibitor or silencing the expression of STAT3 can significantly reduce the progression/incidence of colorectal cancer (CRC), partly through regulating inflammation. Therefore, STAT3 offers a promising therapy. This review evaluates the evidence linking STAT3 with CRC development and analyzes the molecular mechanisms involved, specifically focusing on discussing the roles of natural products or herbal medicines on CRC progression by targeting STAT3. STAT3 activity suppresses tumor development and progression in part by regulating inflammation.
Keywords: Colorectal cancer, natural products, prevention, signal transducers and activators of transcription 3, treatment
|How to cite this article:|
Li W, Chen C, Liu Z, Hua B. Targeting Signal Transducer and Activator of Transcription 3 for Colorectal Cancer Prevention and Treatment with Natural Products. Cancer Transl Med 2016;2:48-54
|How to cite this URL:|
Li W, Chen C, Liu Z, Hua B. Targeting Signal Transducer and Activator of Transcription 3 for Colorectal Cancer Prevention and Treatment with Natural Products. Cancer Transl Med [serial online] 2016 [cited 2020 Sep 25];2:48-54. Available from: http://www.cancertm.com/text.asp?2016/2/2/48/181435
Weidong Li and Cihui Chen contributed equally to this work and are co-first authors
| Introduction|| |
Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most common cause of cancer-related mortality. , Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease are linked to the incidence of CRC. 
Signal transducer and activator of transcription (STAT) proteins regulate many aspects of cell growth, survival, and differentiation. There are seven mammalian STAT family members that have been identified as STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5 α and STAT5 β), and STAT6. STAT3 appears to be more generally transcribed than the other members and recent data demonstrate its role in a wide variety of physiological processes.  STAT3 has many roles in physiological processes such as inflammatory signaling, aerobic glycolysis, and immune suppression and was also the first family member shown to be aberrantly activated in a wide range of both solid and liquid tumors. ,,, The interleukin-6 (IL-6)/STAT3 signaling pathway mediates the proliferative and anti-apoptotic activities required for oncogenesis under inflammatory conditions. ,
STAT3 plays an important role in the STATs family; STAT3 as acute phase response factor in IL-6 signaling was purified in 1994, it is located on chromosome 17q21, contains 24 exons, its full-length DNA 4815 bp.  Relative molecular weight of STAT3 protein is 92,000 Da composed of 750-795 amino acids, which exists as four isomers: STAT3 α, STAT3 β, STAT3 g, and STAT3 d.  Structurally STAT3 protein consists of seven main functional parts: N-tetrameric terminal domains (NH 2 ), coiled-coil domain (CCD), DNA-binding domain (DBD), linking area (linker domain), SH2 region, SH3 region, and C-terminal transcriptional activation domain (TAD). Their functions are as follows: NH 2 participates in STAT tetramer technology; CCD offers to regulate the site of action record factors and regulatory proteins; DBD specially directed for the original binding sequences of inteferon-γ palindromic sequence; DNA-binding domain functions as linking area stabilizer; SH2 region involved in STAT3 dimer formation and tyrosine phosphorylation of STAT3; TAD is involved in transcriptional activation of serine area (or phosphorylation of tyrosine phosphorylation near to C-terminal), activating STAT3 and thus regulating target genes transcription. ,,, STAT3 followed by functional area phase SH2 interaction forms homo- or hetero-dimers which then translocate into the nucleus recognizes specific DNA fragment and binds to it to play its transcriptional regulation roles. ,,
In this review, we will mainly discuss the role of STAT3 in CRC, the co-relationship of STAT3 with CRC incidence and STAT3 as a target for CRC prevention and treatment.
| Signal Transducer and Activator of Transcription 3 and Colorectal Cancer|| |
STAT3 is a key regulator of tumor initiation and progression in CRC, , which regulates proliferation, survival, inflammation, and angiogenesis related to tumor and thus resulting in carcinogenesis and cancer progression. ,,,, In clinical cases of CRC, STAT3 activation is negatively correlated with clinical efficacy and is associated with the prognosis of CRC. , Blocking STAT3 expression induces cancer cell apoptosis and inhibits tumor growth in vivo. ,,,,,,,,,,,,
Inflammatory cytokines in tumor microenvironment have long been thought to increase cancer metastasis. Studies have shown that IL-6 increases the incidence of CRC and its progression was related to STAT3 activation. STAT3 activation further causes the activation of its downstream targets, such as the intestinal mucosa injury-related proteins regeneration-related proteins, and cancer-related genes. ,, Tumor necrosis factor alpha and IL-1β are required in the activation of chronic inflammation. They induce inflammation associated cancer mainly through activating nuclear factor-kappa B pathway; while IL-6 promotes chronic inflammation of the colon and stomach to develop cancer mainly by Stat3 excessive activation. ,,,,
Recent studies have shown that IL-6 was involved in several stages of tumor progression including the tumor initiation, progression, and metastasis, which resulted in activation of transcription factor STAT3 in CRC. It is known that STAT3 activation is correlated with IL-6 secretion.  In the early stages of tumor, in patients with CRC, IL-6 is mainly secreted from macrophages and dendritic cells in the lamina propria, while in patients with advanced CRC, IL-6 is mainly derived from CD4+ T cells;  this may be due to the presence of T-cells in the environment of high inflammatory tumors, but epidermal cells are killed in the process of tumor progression.  IL-6 activation in the early stage of CRC increases tumorigenesis and is accompanied by an increase in the level of phosphorylation of STAT3.  Increased activity of STAT3 in patients with CRC could induce the expression of anti-apoptotic protein Bcl-2 and Bcl-xL, whereas inhibition of STAT3 signaling pathway could suppress the same to induce cancer cells apoptosis. 
STAT3 and both Janus kinase 1 (JAK1) and 2 are involved in CRC cell growth, survival, invasion, and migration by regulating gene expression, such as Bcl-2, p1 (6ink4a), p21 (waf1/cip1), p27 (kip1), E-cadherin, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs).  At the same time, STAT3 activation also regulates tissue factors (such as Hsp70, S100A9, etc.), cell cycle regulators (such as cyclin D1, c-factor Myc, etc.), and proteins related to anti-tumor angiogenesis (basic fibroblast growth factor, VEGF, etc.). ,
| Signal Transducer and Activator of Transcription 3 Expression and Regulation|| |
STAT3 is a latent cytoplasmic transcription factor, induced by a variety of upstream signals including growth factors, cytokines, and nonreceptor tyrosine kinases. , Upon activation by tyrosine phosphorylation, STAT3 forms dimers which translocate to the nucleus and regulate transcription of target genes. Under normal physiological conditions, STAT3 activity is tightly controlled; however, intracellular signaling pathways involving STAT3 are frequently constitutively activated in many different human primary tumors. Numerous STAT3 target genes have been identified including Bcl-2, Bcl-xL, p21, cyclin D1, survivin, and VEGF, which are related to tumor cell proliferation, apoptosis, and angiogenesis. STAT3 and p53 integrating upstream signals are demonstrated as positive and negative regulators of tumor cell proliferation, respectively. STAT3 and p53 also negatively regulate each other. ,,,, It was shown that p53 is the downstream target of STAT3; leukemia inhibitory factor (LIF), which is actively involved in human colorectal cancer condition, has been shown to downregulate p53 protein and vice-versa. LIF downregulates p53 protein levels and function in human CRC cells. The downregulation of p53 by LIF is mediated by the activation of STAT3, which transcriptionally induces inhibition of DNA-binding 1 (ID1). ID1 upregulates MDM2, a key negative regulator of p53, and promotes p53 protein degradation.  Cellular invasiveness is dependent on the balance between two opposing forces: proinvasive oncogenes Src-STAT3 and anti-invasive tumor suppressors, p53-PTEN.  STAT3 activity also influences p53 response genes and affects UV-induced cell growth arrest in normal cells. Furthermore, blocking STAT3 in cancer cells upregulates expression of p53, leading to p53-mediated tumor cell apoptosis. As a point of convergence for many oncogenic signaling pathways, STAT3 is constitutively activated at high frequency in a wide diversity of cancers and is a promising molecular target for cancer therapy. Thus, repression of p53 expression by STAT3 is likely to have an important role in development of tumors, and targeting STAT3 represents a novel therapeutic approach for p53 reactivation in many cancers lacking p53 activity. 
| Signal Transducer and Activator of Transcription 3 and Interleukin-6|| |
IL-6 is a multi-effective cytokine which binds a soluble IL-6 receptor (sIL-6R) to form IL-6/sIL-6R complex, which then activates cell surface gp130 to induce STAT3 activation. , IL-6 is also a proinflammatory cytokine that is primarily produced by the cells comprising the tumor microenvironment: fibroblasts, myeloid cells, and lymphoid cells. IL-6 plays a key role in promoting the proliferation and inhibiting of apoptosis  as it binds to its receptor (sIL-6R) and coreceptor (glycoprotein 130 or gp130), resulting in the activation of the associated JAKs. Activated JAKs phosphorylate gp130 lead to the recruitment and activation of STAT3. ,,,,,,,,,, The activation of the intracellular JAK/STAT3 signaling pathway, triggered by IL-6, leads to the induction of genes involved in the development of CRC. , The protumorigenic effect of IL-6 is largely mediated by the transcription factor STAT3, and the IL-6/STAT3 cascade is an important regulator of proliferation in tumor cells.  STAT3 is a critical protumorigenic effector for IL-6 signaling. Specific STAT3 ablation in intestinal epithelial cells interferes with tumor formation and growth in colitis-associated cancer. IL-6 is not the sole STAT3 activator, and study has demonstrated that embelin can directly suppress STAT3 activity and IL-6-induced STAT3 activation in colon cancer cells.  Hence, IL-6 along with STAT3 plays an important role in inflammation and carcinogenesis.
| Relative Mechanisms of Signal Transducer and Activator of Transcription 3|| |
The activation of STAT3 is correlated to cancer cell proliferation. Cyclin D1 is a very important cell cycle regulator from G1 phase to S phase and can be regulated by STAT3. The high expression of cyclin D1 indicates the continuously abnormal proliferation of cancer cells. Lassmann et al.  showed that the mRNA level of STAT3 is high positively correlated with the level of cyclin D1 in CRC tissues of 32 patients. Leslie et al.  found that when STAT3 is activated in cells, the levels of cyclin D1 distinctly increased.
Apoptosis is another important mechanism involved in cancer formation and progression. During the process of carcinogenesis, STAT3 can supply survival signal and inhibit cancer cell apoptosis by regulating Bcl-2, Bcl-Xl, Mcl-1, survivin, and other related genes or proteins. 
Hedyotis diffusa Willd extract suppresses cell growth and induces the apoptosis of human fibrosarcoma cells via the inactivation of IL-6/STAT3 signaling pathway.  Embelin suppresses colitis-associated tumorigenesis, and its antitumor effect is partly mediated by limiting IL-6/STAT3 activation and Th17 immune response. 
Invasion and metastasis
Basement membrane and extracellular matrix degradation play a key role in tumor cell invasion and metastasis. MMP is a key regulator in the degradation process of basement membrane. STAT3 activation could significantly enhance the metastatic abilities of low metastatic potential cell lines STAT3; while blockading STAT3 activation with a dominant negative mutant can significantly reduce the expression of MMP-2, thereby inhibiting tumor invasion and metastasis. Moreover, STAT3 reduces inter-cell adhesion ability which promotes tumor cell invasion and metastasis. 
In CRC, higher expression of STAT3 is correlated to the tumor invasion and lymph metastasis as well as the late tumor stages.  Zugowski et al.  found that STAT3 could upregulate MMP-1 by binding either to its promoter or to other transcription factors to form complex, thereby promoting tumor cell infiltration. High expression of MMP-9 and MMP-2 correlates the continuous activation of STAT3 and coordinates to participate in the invasion and metastasis of CRC.  Proinflammatory factors may also increase Twist expression by the activation of STAT3, thereby promoting tumor epithelial-mesenchymal transition and enhancing its ability to metastasis.  It was shown that excessive IL-22, one of the cytokines secreted by Th17 cells, demonstrates both a protective effect and promotion of inflammation in inflammatory promotion effect in IBD through STAT3 signaling activation, and in the colon cancer and ulcerative colitis microenvironment that could lead to tumor growth, inhibition of apoptosis, and promotion of metastasis depending on STAT3 activation. 
Tumor vascular growth
Angiogenesis is a prerequisite for tumor growth and is the foundation for tumor invasion and metastasis.
VEGF is a key factor to induce angiogenesis in CRC and is the direct target gene of STAT3.  Nitidine chloride dose-dependently suppressed VEGF-induced endothelial cell proliferation, migration, and tubular structure formation in vitro and dramatically reduced VEGF-triggered neovascularization in mouse cornea and Matrigel Plugs in vivo. This angiogenesis inhibition mediated by nitidine chloride was well interpreted by the suppression of JAK2/STAT3 signaling and STAT3 DNA-binding activity in endothelial cells. 
| Natural Products Targeting Signal Transducer and Activator of Transcription 3 for Colorectal Cancer and Treatment|| |
As discussed so far, STAT3 is involved in the regulation of many genes during carcinogenesis, which makes it become a promising target for cancer treatment.  In searching for the effective therapy with fewer side effects for CRC prevention and treatment, natural products and alternative medicine are the promising candidates [Table 1].
|Table 1: Natural products extracted from herbal medicines targeting signal transducers and activators of transcription 3 to inhibit the growth of colorectal cancer |
Click here to view
Spica Prunellae has long been used as an important component in many traditional Chinese medicine (TCM) formulae to clinically treat CRC. Spica Prunellae possesses a broad range of anticancer activities due to its ability to affect STAT3 pathway in CRC, and it was found that the inhibitory effect of Spica Prunellae on STAT3 activation resulted in an increase in the pro-apoptotic Bax/Bcl-2 ratio and a decrease in the expression of the pro-proliferative cyclin D1 and CDK4, as well as pro-angiogenic VEGF-A and VEGF receptor-2 in vitro and in vivo. The ethanol extract of H. diffusa Willd (EEHDW) reduced tumor volume and tumor weight, demonstrating that EEHDW can inhibit CRC growth in vivo without apparent adverse effect on the normal activities and body weight loss in animals. In addition, EEHDW treatment suppressed STAT3 phosphorylation in tumor tissues, which in turn resulted in the promotion of cancer cell apoptosis and inhibition of proliferation.  The ethanol extract of Scutellaria barbata D. Don could effectively inhibit the proliferation and promote the apoptosis of human colon carcinoma cells via the modulation of the IL-6/STAT3 signaling pathway and its target genes such as cyclin D1 and B-cell lymphoma-2 in vitro. 
Many TCM and their monomers with heat-clearing and detoxifying roles can significantly inhibit the proliferation and induce the apoptosis of colon cancer cells by regulating STAT3 signaling pathway. Banzhilian (S. barbata D Don) can inhibit the activation of STAT3 in CRC and then inhibit its downstream targets linked with colon cancer cell proliferation and apoptosis in vitro.  Quinazoline alkaloid extracted from bitter beans can inhibit colon cancer cell proliferation and apoptosis by suppressing JAK/STAT3 and PI-3K/AKT signaling pathways in vitro. Xia Ku Cao (Prunella vulgaris Linn) inhibits the proliferation of CRC cells, induces apoptosis in vitro, and suppresses angiogenesis in CRC tissue by inhibiting the phosphorylation of STAT3 in vivo.  Tumor-bearing animal experiments showed that Pien Tze Huang reduces the tumor mass accompanied by the inhibition of the phosphorylation of STAT3 in tumor tissue.  Our study demonstrates that cryptotanshinone can attenuate the phosphorylation of STAT3 in CRC cells and inhibit STAT3-related gene products including cyclinD1, Bcl-2, and survivin in CRC cell lines. The specificity of cryptotanshinone in affecting the viability of tumor cells sparing nontumor cells together with reported low patient toxicity makes cryptotanshinone a strong candidate for combination therapy for the treatment of CRC.  Berberine inhibits CRC invasion and metastasis via the downregulation of COX-2/PGE2-JAK2/STAT3 signaling pathway in vivo.  Butein (3, 4, 2',4'-tetrahydroxychalcone) is a promising natural polyphenolic compound which could induce apoptosis and arrest colorectal tumor formation/progression in xenograft by targeting IL-6/STAT3 signal pathway in vivo.  Oroxylin A inhibits colitis-associated carcinogenesis through modulating IL-6/STAT3 pathway in AOM/dextran sodium sulfate mouse model and HCT-116 cells.  Thymoquinone, a compound isolated from black seed oil (Nigella sativa), has been reported to possess anti-inflammatory and anticancer activities and can induce apoptosis in HCT-116 cells by blocking STAT3 signaling via the inhibition of JAK2- and Src-mediated phosphorylation of EGFR tyrosine kinase in vitro.  Bufalin not only inhibits the growth of colon cancer SW620 cells but also induces apoptosis of SW620 cells. Activation of caspase-3, upregulation of Bax and downregulation of living and Bcl-2, as well as inhibition of JAK-STAT3 signaling pathway might be the important mechanisms for the bufalin-induced apoptosis.  Triptolide, a diterpenoid triepoxide from the TCM herb Tripterygium wilfordii Hook F, is used as a potential treatment for autoimmune diseases as well a possible anti-tumor agent. Triptolide can interrupt the IL6R-JAK/STAT pathway that is crucial for cell proliferation, survival, and inflammation, and hence, it might be a candidate for the prevention of colitis-induced colon cancer because it can reduce inflammation and prevent tumor formation and development in vivo. 
Based on the above information, for an effective handling of CRC, it is essential to understand STAT3 related upstream and downstream target genes of STAT3 through genetic screening in patients and then choose effective ingredients from herbal medicine to block the mutation target genes and proteins.
| Conclusion|| |
Aberrant activation of STAT3 presenting in various solid tumors and hematological malignancies is linked with tumor cell proliferation, differentiation, invasion, and metastasis. In recent years, more and more studies have shown that many STAT3 inhibitory molecules STAT3 exist in natural medicines.
Inflammatory microenvironment plays a key role in multiple processes of the progression of colon cancer which can be counteracted by many anti-inflammatory treatments that acts by targeting STAT3. TCM has been used for hundreds of years to prevent and treat many maladies including cancer. The use of TCM has been linked to low incidence of certain cancers. Interestingly, many of the herbal remedies historically used in TCM have been used to alleviate inflammation, and recent reports contribute this to the anticancer activities seen with these compounds. This also provides us an opportunity to discover effective therapeutic compounds, targeting STAT3 from herbal medicines with anti-inflammation characters.
Furthermore, there are other indirect effects of STAT3 inhibition that waits to be investigated. However, many of the studies are based on in vitro experimental research or animal studies, and almost no clinical studies are carried out. Therefore, additional studies are necessary before STAT3 inhibitors can be exploited in clinical use.
Financial support and sponsorship
This work was partly supported by National Natural Science Foundation of China (No. 81273718 and 81102587) and China Postdoctoral Science Foundation (No. 2012T50199).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Donald JJ, Burhenne HJ. Colorectal cancer. Can we lower the death rate in the 1990s? Can Fam Physician
1993; 39: 107-14.
Rooney PS, Clarke PA, Gifford KA, Hardcastle JD, Armitage NC. The identification of high and low risk groups for colorectal cancer using rectal mucosal crypt cell production rate (CCPR). Br J Cancer
1993; 68 (1): 172-5.
Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol
2004; 287 (1): G7-17.
Zhang H, Wang S, Zhang YC, Ye YJ, Cui ZR, Fang WG. Correlation between Stat3 signal transduction pathway and expression of cyclooxygenase-2 in colorectal cancer cells. Zhonghua Yi Xue Za Zhi
2005; 85 (41): 2899-904.
Jing N, Li Y, Xu X, Sha W, Li P, Feng L, Tweardy DJ. Targeting Stat3 with G-quartet oligodeoxynucleotides in human cancer cells. DNA Cell Biol
2003; 22 (11): 685-96.
Ma X, Wang S, Du R, Ye Y, Wang S, Yan F, Cui Z. Stat3 signal transduction pathway orchestrates G1 to S cell cycle transition in colon cancer cells. Beijing Da Xue Xue Bao
2003; 35 (1): 50-3. (in Chinese)
Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene
2003; 22 (3): 319-29.
DeMiguel F, Lee SO, Lou W, Xiao X, Pflug BR, Nelson JB, Gao AC. Stat3 enhances the growth of LNCaP human prostate cancer cells in intact and castrated male nude mice. Prostate
2002; 52 (2): 123-9.
Fagard R, Metelev V, Souissi I, Baran-Marszak F. STAT3 inhibitors for cancer therapy: have all roads been explored? JAKSTAT
2013; 2 (1): e22882.
Fan Y, Mao R, Yang J. NF-kappaB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell
2013; 4 (3): 176-85.
Lutticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A, Harpur AG, Wilks AF, Yasukawa K, Taga T. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science
1994; 263 (5143): 89-92.
Benekli M, Baer MR, Baumann H, Wetzler M. Signal transducer and activator of transcription proteins in leukemias. Blood
2003; 101 (8): 2940-54.
Walker S, Wang C, Walradt T, Hong BS, Tanner JR, Levinsohn JL, Goh G, Subtil A, Lessin SR, Heymann WR, Vonderheid EC, King BA, Lifton RP, Choi J. Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. Blood
2016; 127 (7): 948-51.
Yeh JE, Frank DA. STAT3-interacting proteins as modulators of transcription factor function: implications to targeted cancer therapy. ChemMedChem
2015. doi: 10.1002/cmdc.201500482.
Zhang HF, Chen Y, Wu C, Wu ZY, Tweardy DJ, Alshareef A, Liao LD, Xue YJ, Wu JY, Chen B, Xu XE, Gopal K, Gupta N, Li EM, Xu LY, Lai R. The opposing function of STAT3 as an oncoprotein and tumor suppressor is dictated by the expression status of STAT3beta in esophageal squamous cell carcinoma. Clin Cancer Res
2016; 22 (3): 691-703.
Wilson RP, Ives ML, Rao G, Lau A, Payne K, Kobayashi M, Arkwright PD, Peake J, Wong M, Adelstein S, Smart JM, French MA, Fulcher DA, Picard C, Bustamante J, Boisson-Dupuis S, Gray P, Stepensky P, Warnatz K, Freeman AF, Rossjohn J, McCluskey J, Holland SM, Casanova JL, Uzel G, Ma CS, Tangye SG, Deenick EK. STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function. J Exp Med
2015; 212 (6): 855-64.
Wake MS, Watson CJ. STAT3 the oncogene - Still eluding therapy? FEBS J
2015; 282 (14): 2600-11.
Levy DE, Inghirami G. STAT3: a multifaceted oncogene. Proc Natl Acad Sci U S A
2006; 103 (27): 10151-2.
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr. Stat3 as an oncogene. Cell
1999; 98 (3): 295-303.
Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L, Karin M. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer cell
2009; 15 (2): 103-13.
Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev
2010; 21 (1): 11-9.
Haftchenary S, Luchman HA, Jouk AO, Veloso AJ, Page BD, Cheng XR, Dawson SS, Grinshtein N, Shahani VM, Kerman K, Kaplan DR, Griffin C, Aman AM, Al-Awar R, Weiss S, Gunning PT. Potent targeting of the STAT3 protein in brain cancer stem cells: a promising route for treating glioblastoma. ACS Med Chem Lett
2013; 4 (11): 1102-7.
Han Z, Feng J, Hong Z, Chen L, Li W, Liao S, Wang X, Ji T, Wang S, Ma D, Chen G, Gao Q. Silencing of the STAT3 signaling pathway reverses the inherent and induced chemoresistance of human ovarian cancer cells. Biocheml Biophys Res Commun
2013; 435 (2): 188-94.
Han Z, Wang X, Ma L, Chen L, Xiao M, Huang L, Cao Y, Bai J, Ma D, Zhou J, Hong Z. Inhibition of STAT3 signaling targets both tumor-initiating and differentiated cell populations in prostate cancer. Oncotarget
2014; 5 (18): 8416-28.
Ho PL, Lay EJ, Jian W, Parra D, Chan KS. Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer. Cancer Res
2012; 72 (13): 3135-42.
Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophy Res Commun
2005; 335 (2): 292-9.
Corvinus FM, Orth C, Moriggl R, Tsareva SA, Wagner S, Pfitzner EB, Baus D, Kaufmann R, Huber LA, Zatloukal K, Beug H, Ohlschläger P, Schütz A, Halbhuber KJ, Friedrich K. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia
2005; 7 (6): 545-55.
Chongqiang Z, Wenlong W, Wenying Y, David J, Yina W, Haiyan M, Hui X, Hua Q, Cuntai Z, Jiagao L, Sheng L, Chenglong L, Jiayuh L, Li L. A novel small molecule STAT3 inhibitor, LY5, inhibits cell viability, colony formation, and migration of colon and liver cancer cells. Oncotarget
2016. doi: 10.18632/oncotarget.7338.
Bak Y, Kwon T, Bak IS, Hong J, Yu DY, Yoon DY. IL-32theta inhibits stemness and epithelial-mesenchymal transition of cancer stem cells via the STAT3 pathway in colon cancer. Oncotarget
2016. doi: 10.18632/oncotarget.7007.
Lu YM, Chen W, Zhu JS, Chen WX, Chen NW. Eriocalyxin B blocks human SW1116 colon cancer cell proliferation, migration, invasion, cell cycle progression and angiogenesis via the JAK2/STAT3 signaling pathway. Mol Med Rep
2016. doi: 10.3892/mmr.2016.4800.
Kim DH, Park KW, Chae IG, Kundu J, Kim EH, Kundu JK, Chun KS. Carnosic acid inhibits STAT3 signaling and induces apoptosis through generation of ROS in human colon cancer HCT116 cells. Mol Carcinog
2015. doi: 10.1002/mc.22353.
Kang Y, Nian H, Rajendran P, Kim E, Dashwood WM, Pinto JT, Boardman LA, Thibodeau SN, Limburg PJ, Lohr CV, Bisson WH, Williams DE, Ho E, Dashwood RH. HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. Cell Death Dis
2014; 5: e1476.
Park KW, Kundu J, Chae IG, Kim DH, Yu MH, Kundu JK, Chun KS. Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells. Int J Oncol
2014; 44 (4): 1309-15.
Cross-Knorr S, Lu S, Perez K, Guevara S, Brilliant K, Pisano C, Quesenberry PJ, Resnick MB, Chatterjee D. RKIP phosphorylation and STAT3 activation is inhibited by oxaliplatin and camptothecin and are associated with poor prognosis in stage II colon cancer patients. BMC Cancer
2013; 13: 463.
Nishimoto A, Kugimiya N, Hosoyama T, Enoki T, Li TS, Hamano K. JAB1 regulates unphosphorylated STAT3 DNA-binding activity through protein-protein interaction in human colon cancer cells. Biochem Biophys Res Commun
2013; 438 (3): 513-8.
Yang Z, Huo S, Shan Y, Liu H, Xu Y, Yao K, Li X, Zhang X. STAT3 repressed USP7 expression is crucial for colon cancer development. FEBS Lett
2012; 586 (19): 3013-7.
Lin L, Fuchs J, Li C, Olson V, Bekaii-Saab T, Lin J. STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH(+)/CD133(+) stem cell-like human colon cancer cells. Biochem Biophys Res Commun
2011; 416 (3-4): 246-51.
Hamilton KE, Simmons JG, Ding S, Van Landeghem L, Lund PK. Cytokine induction of tumor necrosis factor receptor 2 is mediated by STAT3 in colon cancer cells. Mol Cancer Res
2011; 9 (12): 1718-31.
Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C, Lin J. STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res
2011; 71 (23): 7226-37.
Lee JH, Kim C, Sethi G, Ahn KS. Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel. Oncotarget
2015; 6 (8): 6386-405.
Lee MH, Kundu JK, Keum YS, Cho YY, Surh YJ, Choi BY. Resveratrol inhibits IL-6-induced transcriptional activity of AR and STAT3 in human prostate cancer LNCaP-FGC cells. Biomol Ther
2014; 22 (5): 426-30.
Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, Yoshimura A, Reindl W, Sipos B, Akira S, Schmid RM, Algül H. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell
2011; 19 (4): 456-69.
Liu Y, Fuchs J, Li C, Lin J. IL-6, a risk factor for hepatocellular carcinoma: FLLL32 inhibits IL-6-induced STAT3 phosphorylation in human hepatocellular cancer cells. Cell Cycle
2010; 9 (17): 3423-7.
Liu Y, Lin J. Blocking the IL-6-STAT3 signaling pathway: potential liver cancer therapy. Future Oncol
2011; 7 (2): 161-4.
Li Y, de Haar C, Chen M, Deuring J, Gerrits MM, Smits R, Xia B, Kuipers EJ, van der Woude CJ. Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut
2010; 59 (2): 227-35.
Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A, Burg J, Strand S, Kiesslich R, Huber S, Nishimoto N, Yoshizaki K, Kishimoto T, Galle PR, Blessing M, Rose-John S, Neurath MF. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity
2004; 21 (4): 491-501.
Grivennikov SI, Karin M. Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis
2011; 70 Suppl 1: i104-8.
Lassmann S, Schuster I, Walch A, Gobel H, Jutting U, Makowiec F, Hopt U, Werner M. STAT3 mRNA and protein expression in colorectal cancer: effects on STAT3-inducible targets linked to cell survival and proliferation. J Clin Pathol
2007; 60 (2): 173-9.
Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ, Lu R, Chen YX, Fang JY. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia
2008; 10 (3): 287-97.
Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer
2009; 9 (11): 798-809.
Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell
2014; 26 (2): 207-21.
Barre B, Vigneron A, Perkins N, Roninson IB, Gamelin E, Coqueret O. The STAT3 oncogene as a predictive marker of drug resistance. Trends Mol Med
2007; 13 (1): 4-11.
Masuda A, Kamai T, Abe H, Arai K, Yoshida K. Is Stat3 and/or p53 mRNA expression a prognostic marker for renal cell carcinoma? Biomed Res
2009; 30 (3): 171-6.
Seo HS, Choi HS, Kim SR, Choi YK, Woo SM, Shin I, Woo JK, Park SY, Shin YC, Ko SG. Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFkappaB signaling in HER2-overexpressing breast cancer cells. Mol Cell Biochem
2012; 366 (1-2): 319-34.
Choy MK, Movassagh M, Siggens L, Vujic A, Goddard M, Sanchez A, Perkins N, Figg N, Bennett M, Carroll J, Foo R. High-throughput sequencing identifies STAT3 as the DNA-associated factor for p53-NF-kappaB-complex-dependent gene expression in human heart failure. Genome Med
2010; 2 (6): 37.
Sainz-Perez A, Gary-Gouy H, Gaudin F, Maarof G, Marfaing-Koka A, de Revel T, Dalloul A. IL-24 induces apoptosis of chronic lymphocytic leukemia B cells engaged into the cell cycle through dephosphorylation of STAT3 and stabilization of p53 expression. J Immunol
2008; 181 (9): 6051-60.
Lee TL, Yeh J, Friedman J, Yan B, Yang X, Yeh NT, Van Waes C, Chen Z. A signal network involving coactivated NF-kappaB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. Int J Cancer
2008; 122 (9): 1987-98.
Yu H, Yue X, Zhao Y, Li X, Wu L, Zhang C, Liu Z, Lin K, Xu-Monette ZY, Young KH, Liu J, Shen Z, Feng Z, Hu W. LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers. Nat Commun
2014; 5: 5218.
Mukhopadhyay UK, Mooney P, Jia L, Eves R, Raptis L, Mak AS. Doubles game: Src-Stat3 versus p53-PTEN in cellular migration and invasion. Mol Cell Biol
2010; 30 (21): 4980-95.
Niu G, Wright KL, Ma Y, Wright GM, Huang M, Irby R, Briggs J, Karras J, Cress WD, Pardoll D, Jove R, Chen J, Yu H. Role of Stat3 in regulating p53 expression and function. Mol Cell Biol
2005; 25 (17): 7432-40.
Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J. The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol
2011; 90 (6-7): 484-94.
Kovacs E. Investigation of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130) in sera of cancer patients. Biomed Pharmacother
2001; 55 (7): 391-6.
Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res
2014; 2014: 149185.
Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J
2003; 374(Pt 1): 1-20.
Rosell R, Bertran-Alamillo J, Molina MA, Taron M. IL-6/gp130/STAT3 signaling axis in cancer and the presence of in-frame gp130 somatic deletions in inflammatory hepatocellular tumors. Future Oncol
2009; 5 (3): 305-8.
McLoughlin RM, Jenkins BJ, Grail D, Williams AS, Fielding CA, Parker CR, Ernst M, Topley N, Jones SA. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc Natl Acad Sci U S A
2005; 102 (27): 9589-94.
Fielding CA, McLoughlin RM, McLeod L, Colmont CS, Najdovska M, Grail D, Ernst M, Jones SA, Topley N, Jenkins BJ. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J Immunol
2008; 181 (3): 2189-95.
Mejias-Luque R, Peiro S, Vincent A, Van Seuningen I, de Bolos C. IL-6 induces MUC4 expression through gp130/STAT3 pathway in gastric cancer cell lines. Biochim Biophys Acta
2008; 1783 (10): 1728-36.
Yan B, Wei JJ, Yuan Y, Sun R, Li D, Luo J, Liao SJ, Zhou YH, Shu Y, Wang Q, Zhang GM, Feng ZH. IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation. J Immunol
2013; 190 (11): 5882-93.
Anglesio MS, George J, Kulbe H, Friedlander M, Rischin D, Lemech C, Power J, Coward J, Cowin PA, House CM, Chakravarty P, Gorringe KL, Campbell IG; Australian Ovarian Cancer Study Group, Okamoto A, Birrer MJ, Huntsman DG, de Fazio A, Kalloger SE, Balkwill F, Gilks CB, Bowtell DD. IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res
2011; 17 (8): 2538-48.
Zou M, Zhang X, Xu C. IL6-induced metastasis modulators p-STAT3, MMP-2 and MMP-9 are targets of 3,3′- diindolylmethane in ovarian cancer cells. Cell Oncol (Dordr)
2016; 39 (1): 47-57.
van der Zee M, Sacchetti A, Cansoy M, Joosten R, Teeuwssen M, Heijmans-Antonissen C, Ewing-Graham PC, Burger CW, Blok LJ, Fodde R. IL6/JAK1/STAT3 signaling blockade in endometrial cancer affects the ALDHhi/CD126+stem-like component and reduces tumor burden. Cancer Res
2015; 75 (17): 3608-22.
Do EJ, Hwang SW, Kim SY, Ryu YM, Cho EA, Chung EJ, Park S, Lee HJ, Byeon JS, Ye BD, Yang DH, Park SH, Yang SK, Kim JH, Myung SJ. Suppression of colitis-associated carcinogenesis through modulation of IL-6/STAT3 pathway by balsalazide and VSL#3. J Gastroenterol Hepatol
2015. doi: 10.1111/jgh.13280.
Yang X, Zhang F, Wang Y, Cai M, Wang Q, Guo Q, Li Z, Hu R. Oroxylin A inhibits colitis-associated carcinogenesis through modulating the IL-6/STAT3 signaling pathway. Inflamm Bowel Dis
2013; 19 (9): 1990-2000.
Dai Y, Jiao H, Teng G, Wang W, Zhang R, Wang Y, Hebbard L, George J, Qiao L. Embelin reduces colitis-associated tumorigenesis through limiting IL-6/STAT3 signaling. Mol Cancer Ther
2014; 13 (5): 1206-16.
Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W, Kim YB, Paz K, Darnell JE, Albanese C, Sakamaki T, Pestell R, Bromberg J. Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res
2006; 66 (5): 2544-52.
Bhattacharya S, Ray RM, Johnson LR. STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells. Biochem J
2005; 392(Pt 2): 335-44.
Cui Y, Meng H, Liu W, Wang H, Liu Q. Huaier aqueous extract induces apoptosis of human fibrosarcoma HT1080 cells through the mitochondrial pathway. Oncol Lett
2015; 9 (4): 1590-6.
Rivat C, De Wever O, Bruyneel E, Mareel M, Gespach C, Attoub S. Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell-cell adhesion complexes. Oncogene
2004; 23 (19): 3317-27.
Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Nagayasu T, Sekine I. Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol
2005; 58 (8): 833-8.
Zugowski C, Lieder F, Muller A, Gasch J, Corvinus FM, Moriggl R, Friedrich K. STAT3 controls matrix metalloproteinase-1 expression in colon carcinoma cells by both direct and AP-1-mediated interaction with the MMP-1 promoter. Biol Chem
2011; 392 (5): 449-59.
Teng J, Wang X, Xu Z, Tang N. HBx-dependent activation of twist mediates STAT3 control of epithelium-mesenchymal transition of liver cells. J Cell Biochem
2013; 114 (5): 1097-104.
Jiang R, Wang H, Deng L, Hou J, Shi R, Yao M, Gao Y, Yao A, Wang X, Yu L, Sun B. IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer
2013; 13: 59.
Chen Z, Han ZC. STAT3: a critical transcription activator in angiogenesis. Med Res Rev
2008; 28 (2): 185-200.
Chen J, Wang J, Lin L, He L, Wu Y, Zhang L, Yi Z, Chen Y, Pang X, Liu M. Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Mol Cancer Ther
2012; 11 (2): 277-87.
Masciocchi D, Gelain A, Villa S, Meneghetti F, Barlocco D. Signal transducer and activator of transcription 3 (STAT3): a promising target for anticancer therapy. Future Med Chem
2011; 3 (5): 567-97.
Lin W, Zheng L, Zhuang Q, Zhao J, Cao Z, Zeng J, Lin S, Xu W, Peng J. Spica Prunellae promotes cancer cell apoptosis, inhibits cell proliferation and tumor angiogenesis in a mouse model of colorectal cancer via suppression of stat3 pathway. BMC Complement Altern Med
2013; 13: 144.
Cai Q, Lin J, Wei L, Zhang L, Wang L, Zhan Y, Zeng J, Xu W, Shen A, Hong Z, Peng J. Hedyotis diffusa
Willd inhibits colorectal cancer growth in vivo
via inhibition of STAT3 signaling pathway. Int J Mol Sci
2012; 13 (5): 6117-28.
Jiang Q, Li Q, Chen H, Shen A, Cai Q, Lin J, Peng J. Scutellaria barbata
D. Don inhibits growth and induces apoptosis by suppressing IL-6-inducible STAT3 pathway activation in human colorectal cancer cells. Exp Ther Med
2015; 10: 1602-8.
Lin J, Chen Y, Cai Q, Wei L, Zhan Y, Shen A, Sferra TJ, Peng J. Scutellaria Barbata
D. Don inhibits colorectal cancer growth via suppression of multiple signaling pathways. Integr Cancer Ther
2013; 13 (3): 240-8.
Zhang L, Zheng Y, Deng H, Liang L, Peng J. Aloperine induces G2/M phase cell cycle arrest and apoptosis in HCT116 human colon cancer cells. Int J Mol Med
2014; 33 (6): 1613-20.
Zhuang Q, Hong F, Shen A, Zheng L, Zeng J, Lin W, Chen Y, Sferra TJ, Hong Z, Peng J. Pien Tze Huang inhibits tumor cell proliferation and promotes apoptosis via suppressing the STAT3 pathway in a colorectal cancer mouse model. Int J Oncol
2012; 40 (5): 1569-74.
Li W, Saud SM, Young MR, Colburn NH, Hua B. Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro
. Mol Cell Biochem
2015; 406 (1-2): 63-73.
Liu X, Ji Q, Ye N, Sui H, Zhou L, Zhu H, Fan Z, Cai J, Li Q. Berberine inhibits invasion and metastasis of colorectal cancer cells via COX-2/PGE2 mediated JAK2/STAT3 signaling pathway. PLoS One
2015; 10 (5): e0123478.
Huang YT, Lin CI, Chien PH, Tang TT, Lin J, Chao JI. The depletion of securin enhances butein-induced apoptosis and tumor inhibition in human colorectal cancer. Chem Biol Interact
2014; 220: 41-50.
Kundu J, Choi BY, Jeong CH, Kundu JK, Chun KS. Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and src-mediated phosphorylation of EGF receptor tyrosine kinase. Oncol Rep
2014; 32 (2): 821-8.
Zhu Z, Li E, Liu Y, Gao Y, Sun H, Ma G, Wang Z, Liu X, Wang Q, Qu X, Liu Y, Yu Y. Inhibition of Jak-STAT3 pathway enhances bufalin-induced apoptosis in colon cancer SW620 cells. World J Surg Oncol
2012; 10: 228.
Wang Z, Jin H, Xu R, Mei Q, Fan D. Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression. Exp Mol Med
2009; 41 (10): 717-27.