|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 2019 Jun 16];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.
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