Colorectal cancer is a malignant tumour of the digestive system, more common in the elderly than in younger individuals. The incidence rate in the United States and the European Union is increasing by an average of 4.2% to 4.6% annually. There is emerging evidence that deregulation of the signalling pathway and abnormal expression and activation of genes is the main reason for the development of colorectal cancer. Signal transducer and activator of transcription (STAT3) is a transcription factor of signal transduction and transcriptional activation of target genes which plays important roles in proliferation, differentiation, apoptosis and other physiological processes. It has been confirmed that abnormal activation of STAT3 is involved in the development of tumours, so the identification of STAT3 inhibitors is a promising strategy for cancer chemoprevention and treatment of colorectal cancer. In this review, the roles of STAT3 in the pathogenesis and treatment of colorectal cancer are discussed.
Keywords: STAT3, colorectal cancer, kinase JAK, SOCS proteins
Colorectal cancer (CRC) is the second most common cancer diagnosed in women and the third most common in men. The prevalence of CRC increases at an average rate of 2.5% annually. Moreover, the incidence of CRC worldwide is predicted to increase to 2.5 million new cases in 2035 . Epidemiological studies have shown the strong dependence of the disease incidence on gender, males, and increasing age. Additionally, diet, lifestyle, medications, smoking, obesity and a sedentary lifestyle were associated with an increased risk of CRC. Moreover, genetic changes may play a crucial role in CRC pathogenesis .
CRC develops through a multistage process characterised by the accumulation of aberrant protein expression, which results in the formation of tumour cells . Recently, increasing attention has been focused on transcription factors contributing to oncogenic signalling pathways such as signal transducer and activator of transcription (STAT3) [4,5]. Persistent STAT3 activation is described in several neoplasias, including CRC. Blocking STAT3 in cultured CRC cells inhibits cell proliferation and induces apoptosis . Although STAT3 is required for the survival of normal intestinal epithelial cells, long-term interference with STAT3 activation could promote gastrointestinal damage. Hence, STAT3 is a potential therapeutic target for CRC [7,8].
Structure of STAT3
STAT3 belongs to the STAT family proteins and contains six domains: N-terminal domain (ND), coiled-coil domain (CCD), DNA binding domain (DBD), the linker region, Src homology domain (SH2), and a C-terminal transcriptional activation domain (TAD) (Figure 1). The ND domain stabilises the dimerised STAT3, promoting the formation of tetramers of two STAT3 dimers for more stable binding with DNA. The CCD domain mediates STAT3 direct binding to the receptor and promotes STAT3 phosphorylation on the 705-tyrosine site (Y705). The DBD domain initiates transcriptional activation of the target genes, while the SH2 domain plays a critical role in signal transduction. The TAD domain possesses conserved phosphorylation sites at Tyr705 and Ser727, and SH2 can recognise phosphotyrosine residues, thus are closely related to STAT3 activation [6,9].
STAT3 possess four isoforms: STAT3α, STAT3β, STAT3γ, and STAT3δ, with STAT3α being the most common and consists of ND, CCD, DBD, Linker, SH2 and TAD domains. STAT3α is associated with the proliferation and transformation of cells .
Activation of STAT3
The classical STAT3 signalling pathway is activated through the binding of interleukins, cytokines or growth factors to their corresponding cell surface receptors (Table 1).
|IL-6, IL-7, IL-10, IL-20||leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), interferon γ (IFN- γ), tumour necrosis factor (TNF-α), monocyte-1 chemotactic protein (MCP-1), macrophage inflammatory protein-1α (MIP-1α), stem cell factor (SCF), oncostatin M (OSM)||epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), insulin-like growth factor receptor (IGFR), vascular endothelial growth factor receptor (VEGFR)|
In normal conditions, STAT3 is situated in the cytosol, dimerising and translocating to the nucleus after being activated via phosphorylation of the tyrosine705 residue. In the nucleus, it controls the transcription of several apoptotic and cell cycle regulatory proteins . STAT3 can be activated through Janus kinase (JAK), Ras/mitogen-activated protein kinase (MAPK) and non-receptor tyrosine kinase signalling pathways . The JAK phosphorylates tyrosine residues on STAT3, especially at the Y705 site, leading to activation and dimerisation of STAT3, subsequent transport to the nucleus and binding to the GAS sequence for the initiation of the transcription of target genes . Ras-MAPK phosphorylates the serine residue in STAT3 on S727, which leads to STAT3 dimerisation and its translocation to the nucleus, it also binds to DNA sequences in the promoters of genes . The non-receptor tyrosine kinases such as activated Src kinase and MAPK family members (p36, ERK, JNK), PKCδ, mTOR phosphorylate STAT3 on S727 in the C-terminal domain .
Additionally, STAT3 is also acetylated on a single lysine residue located at position 685 by histone acetyltransferase p300. This acetylation regulates both transcriptional activity and homodimer stability. Other factors, such as UV radiation or sunlight, carcinogen, stress, smoke and infection are also known to play a significant role in STAT3 activation. STAT3 is negatively regulated by specific factors, including the suppressor of cytokine signalling (SOCS) and the protein inhibitor of activated STAT (PIAS) [15,16].
Role of STAT3 in the pathogenesis of colorectal cancer
CRC cells and normal colon cells differ in their hallmarks. In normal cells, the activation of STAT3 is rapid and transient, whereas, in CRC cells, abnormal activation of STAT3 accelerates CRC cell proliferation, blocks their differentiation and inhibits apoptosis which leads to the occurrence and development of CRC. Several studies showed that STAT3 activation contributes to cellular proliferation and survival in the case of CRC. Persistent activation of STAT3 induces upregulated expression of CyclinD1, c-Myc and survivin and accelerates cell cycle progression in colon cancers [17-19]. The STAT3 signalling pathway suppresses apoptosis in CRC through upregulation of the expression of anti-apoptotic proteins such as Bcl-2 (B-cell lymphoma-2), Bcl-xl (B-cell lymphoma-2-like 1), and Mcl1 (myeloid cell leukaemia sequence 1) to prevent apoptosis of CRC cells [20,21]. Inversely, inhibition of STAT3 decreases cell proliferation and promotes apoptosis in CRC . Additionally, recent studies have demonstrated that increased phosphorylated STAT3 (phosphoSTAT3) expression was detected in patients with colorectal carcinoma. However, the prognostic value and clinicopathological parameters of phoshoSTAT3 expression in CRC remain undefined .
Tang et al.  reported that the positive expression of JAK1 and STAT3 proteins in patients with colon cancer was not associated with sex, age, tumour differentiation degree and neurovascular invasion, but was dependent on the clinical stage of cancer, tumour infiltration depth and lymph node metastasis. The survival time of CRC patients with positivelyexpressed JAK1 and STAT3 proteins wassignificantly shorter compared to patients with negativelyexpressed JAK1 and STAT3. Thus, the JAK/STAT signal may be used as a novel tumour marker and prognostic factor for the diagnosis, assessment and prognosis of colon cancer .
STAT3 promotes cell invasion by activating the transcription of matrix metalloproteinases, mainly MMP-2 and MMP-9. In the case of CRC, a correlation between increased MMP-2 and MMP-9 expression and a poor outcome has been proven . Several studies refer to the utility of serum MMPs as markers for CRC invasion. Dragutinović et al.  confirmed the higher levels of MMP-2 and MMP-9 proteins in the sera of patients with CRC compared to controls with no CRC. Additionally, Kryczka et al.  described the upregulation of MMP-2 expression in invasive CRC. The opposite effect was observed in the case of MMP-12, which is also called metalloelastase, which does not belong to any of the MMP subfamilies. According to the studies in animal and human models, increased MMP-12 expression is associated with both reduced tumour growth and increased overall survival [27,28].
STAT3 activation can also contribute to angiogenesis through its effects on vascular endothelial growth factor (VEGF) . However, there is still controversy in terms of the relationship between serum VEGF and VEGF receptor (VEGF-R) tumour expression in CRC . Evidence from preclinical and clinical studies indicates that VEGF is the predominant angiogenic factor in human CRC and is associated with the formation of metastases and poor prognosis .
The JAK/STAT/SOCS-signalling pathway plays a critical role in immune response and regulation of inflammation. Additionally, components of the pathway, such as STAT3, have been shown to promote cell growth and survival through impairment of the expression of genes involved in apoptosis, cell cycle regulation and angiogenesis . SOCS3 is an important signal inhibition factor in the JAK2/STAT3 pathway. The reduction or deletion of SOCS3 expression causes sustained activation of STAT3 in many malignant tumours . Other studies indicate that posphoSTAT3 in CRC is higher than in surrounding tissues, whereas the expression of SOCS3 is lower or absent in CRC tissues. The activation of this signalling pathway promotes the transformation of colitis to CRC. SOCS3 protein inhibited the activation of the JAK/STAT3 pathway by negative feedback regulation of tyrosine phosphorylation of STAT3, which inhibits the growth of tumour cells. STAT3 activation also promoted hypermethylation of SOCS3 gene promoters in DLD1, HT-29 and SW480 cancer cells .
STAT3 as a target in CRC therapy
As STAT3 plays an important role in the development of CRC, it could be used as an essential target in the diagnosis and treatment of CRC. These inhibitors are not implemented in clinical practice but are suggested to be useful. However, clinical studies are required to assess their usefulness, efficiency and potential anticancer activities.
Figure 2 presents the chemical structure of potential inhibitors of STAT3. In this review, we focus on the representatives of different groups of compounds possessing the possible implications of targeting STAT3 in colon cancer. Moreover, the mechanism of STAT3 activation is multifaced, thus Figure 3 presents the suggested therapeutic intervention strategy in the STAT3 pathway during CRC therapy.
Nowadays, STAT3 inhibitors can be classified as indirect and direct (Table 2). The indirect strategy can block molecules and induce the STAT3 pathway, indirectly inhibiting the signal transduction functions of STAT3, mostly through inhibiting the function of JAKs, in turn, there are several direct strategies according to different target domains, including the SH2 domain [35-37].
Salidroside is a glucoside extracted from Rhodiola rosea , which inhibits the proliferation and cell cycle and reduces migration and invasion of colon cancer SW1116 cells through blocking the phosphorylation of JAK/STAT3 . Moreover, Li and Chen  suggest that salidroside downregulates phosphoSTAT3 in HCT116 cells, which is correlated with the induction of autophagy.
Bufalin is a steroid isolated from Chinese toad venom, which inhibits JAK/STAT3 signalling through decreasing the level of phosphoSTAT3 and downregulates the Bcl-2 protein. Bufalin blocks the proliferation of colon adenocarcinoma SW620 cells and induces G2/M cell cycle arrest of these cells [40,41]. Similar results were reported by Qiu et al. , that bufalin reduces the viability of HCT116 cells in a dose- and time-dependent manner.
Berberin is an alkaloid isolated from Hydrastis canadensis and can decrease phosphorylation of JAK and STAT3 proteins in CRC cells . Other studies demonstrated that berberin affects the expression of MMP-2 and MMP-9, but the mechanism has not been elucidated [44,45]. Liu et al.  argue that berberin reduces COX-2/PGE2 levels, consequently decreasing JAK2/STAT3 activation, leading to dampened expression of downstream target genes MMP-2 and MMP-9, reducing invasiveness and metastasis in CRC. A similar effect was presented by Hu et al.  and Hallajzadeh et al. , where the reduction in the JAK2/STAT3 signalling as a consequence of attenuating the COX-2/PGE2 expression by berberin was observed.
Cryptotanshinone is a quinoid diterpene isolated from Salvia miltiorrhiza Bunge. It inhibits the activation of STAT3 pathways through inactivating phosphorylation of STAT3 in SW480, HCT116 and LOVO CRC cell lines. Moreover, cryptotanshinoneattenuates the expression of Bcl-2, CyclinD1 and survivin in HCT116 and SW480 cells. The mechanism of action of cryptotanshinone by direct interaction with STAT3 can also rely on the inhibition of EGFR phosphorylation at higher doses of cryptotanshinone .
Bruceantinol is a triterpenoid isolated from Brucinea javanica, which reduces the level of phosphorylated STAT3 and downstream target expression of Mcl-1, c-Myc, andsurvivin in vitro. A reduction of phosphoSTAT3 was observed in mice with CRC xenografts treated with bruceantinol .
Trichostatin A is a hydroxamic acid produced by Streptomyces hygroscopicus and an inhibitor of class I and II histone deacetylases. The hyperacetylation of histones is associated with SOCS1 and SOCS3 promoters in CRC cells . According to Xiong et al. , trichostatin A can increase the level of SOCS1 and SOCS3 expression in SW1116 and HT-29 colon cancer cell lines. Consequently, it negatively modulates the JAK2/STAT3 pathway, subsequently downregulating Bcl-2 and survivin and decreases growth and apoptosis of CRC cells.
Ursolic acid is a pentacyclic triterpenoid, abundant in apples, pears and prunes . Studies conducted by Wang et al.  confirmed that ursolic acid selectively inhibits STAT3 phosphorylation at Y705 in CRC cell lines, HT-29, HCT116 and SW480. Moreover, some studies confirmed the antiapoptotic properties of ursolic acid in HT-29 cells via inhibition of Bcl-xl, Bcl-2 and Cyclin D1 expression [53,54].
Resveratrolis a plant polyphenol naturally occurring in grapes, red wine, and peanuts . It can inhibit cell proliferation and promote cell apoptosis via the STAT3 signalling pathway in DLD1 and HCT15 colon cancer cells. Li et al.  demonstrated that resveratrol inhibits cell growth in CRC by inhibiting the serine/threonine-protein kinase AKT and its downstream signalling targets. AKT serves as an upstream regulator of STAT3. Additionally, the expression of phosphorylation of STAT3 at the Tyr705 site was suppressed by treatment with resveratrol in a dose-dependent manner .
Apigenin is a type of flavone identified in several types of berries and vegetables, which inhibits the nuclear localisation of STAT3 through the reduction of the expression of phosphoSTAT3 (Tyr705) in HCT116 colon cancer cells .
Genistein is a major isoflavone in soy and soy-based food products that are regularly consumed in Asian countries . Genistein promotes apoptosis in HT-29 colon cancer cells by modulating caspase-3 and p38 MAPK signalling pathway . Genistein also abolished the activation of STAT3, preventing translocation into the nucleus by downregulating the activity of JNK .
Myricetin is a common dietary flavonoid abundantly found in plants. It deregulates the JAK1/STAT3 signalling pathway that controls many processes such as cell growth, differentiation, senescence and apoptosis . Myricetin directly binds with the catalytic domain of the JAK1 protein and inhibits the phosphorylation of STAT3 and JAK1. Moreover, myricetin has been found to increase EGF-induced autophosphorylation of EGFR at Tyr845, Tyr992, Tyr1045, Tyr1068, and Tyr1173, as well as inhibit the autophosphorylation of endogenous EGFR sites. The results indicated that myricetin exerts its chemopreventive effect by directly interacting with JAK1 and STAT3 proteins .
Oroxylin A is an O-methylated flavone found in the roots of Scutellaria baicalensis. It inhibits colitis-associated carcinogenesis through modulating the IL-6/STAT3 pathway in AOM/DSS mouse model and HCT116 cells. This study confirmed that oroxylin A induces Bax and Bcl-2 binding in colon cancer Caco-2 cells .
Sophoraflavanone G is a plant material isolated from Sophora leachiana, S. exigua or S. moorcroftiana. S. pachycarpa or S. flavescens. Treatment ofHCT116 cells with this small-molecule significantly inhibited tyrosine phosphorylation of STAT3, as confirmed by western blot analysis, where the level of phosphoSTAT3 protein was decreased in comparison to the control .
The ethanol extract of Prunella vulgaris L., termed Spica Prunellae, is a well-known traditional Chinese formulation, which can inhibit the STAT3 phosphorylation of Y705, increase the Bax/Bcl-2 ratio, reduce Cyclin D1 and subsequently inhibit CRC cell proliferation and promote apoptosis [64-66].
Benzylidenetetralones are synthetic, cyclic chalcone analogues . Natural and synthetic chalcones have also shown anticancer activity caused by their inhibitory potential against targets such as the JAK/STAT signalling pathway . Benzylidenetetralones decrease the expression of Bcl-xl, consequently induc cell cycle arrest and apoptosis in the HCT116 CRC cell line .
Flubendazole is a well-known anthelmintic drug, which blocks IL6-induced nuclear translocation of STAT3, leading to the inhibition of the transcription of STAT3 target genes, such as MCL1 and VEGF. Flubendazole inhibition of STAT3 phosphorylation is partly dependent on the upstream kinases JAK2 and JAK3. Also, flubendazole reduces the expression of P-mTOR, P62, Bcl-2, and upregulates Beclin1 and LC3-I/II, major autophagy-related genes, thereby inducing potent cell apoptosis in CRC cells. Furthermore, flubendazole displays a synergistic effect with the chemotherapeutic agent 5-fluorouracil in the treatment of CRC .
Nifuroxazide isa nifuran antibiotic, which downregulates the phosphorylation of tyrosine residues (Y705) on STAT3 as well as impairing the expression of MMP-2 and MMP-9 in HCT116 and HT-29 human CRC cell lines .
AG-490 is a pharmacological inhibitor of kinase JAK2, which decreases VEGF secretion in SW1116 and HT-29 cells, functioning likes the JAK/STAT3 pathway in angiogenesis . Additionally, the downregulation of phosphoJAK1, phosphoJAK2 and phosphoSTAT3 was observed after treatment with AG490. This leads to a decline in Bcl-2 and survivin expression [71,72]. Furthermore, STAT3 inhibition by AG-490 treatment has been found to increase cell sensitivity to chemotherapeutic agents .
Curcumin is a natural polyphenol, the yellow pigment in Curcuma longa L. It reduces binding of STAT3 to DNA in CRC cells , thereby abrogating its phosphorylation and nuclear translocation, as well as the subsequent expression of target genes. This approach has mainly focused on targeting the SH2 domain, an important domain by which STAT3 maintains its biological functions .
Napabucasin was the first compound to undergo a series of clinical trials (NCT03522649, NCT02753127, NCT01776307, NCT02851004, NCT01830621, NCT02641873) to determine its efficacy and safety in patients with metastatic CRC . A napabucasin derivative with a 2-(piperidin-1-yl)ethylamino-group substituted at the R2 position significantly inhibited tumour growth in a mouse model. Molecular docking suggested that this compound bound to the SH2 domain of STAT3 in CT26 colon carcinoma mouse cell line .
Ganetespib is a small-molecule inhibitor of heat shock protein 90 (HSP90) activity. Ganji et al.  demonstrated that ganetespib inhibits STAT3 and disrupts angiogenesis of CRC cell lines HCT116 and HT-29, also downregulating the expression of VEGF transcription factors, hypoxia-inducible factor 1-α (HIF-1α) and STAT3. Both STAT3 and HIF-1α are dependent on HSP90 and transcribe VEGF, therefore, HSP90 inhibition by ganetespib also affects the expression of HIF1α and STAT3, leading to decreased transcription of pro-angiogenic cytokines such as VEGF in CRC .
STAT3 is an important signal transducer and activator of transcription which is widely involved in numerous cellular physiological processes, such as proliferation, differentiation and apoptosis. Available data indicate that STAT3 is involved in the pathogenesis of colorectal cancer, hence, it may be useful in colorectal cancer diagnosis, treatment and prognosis. However, further studies are needed to determine if STAT3 is of use in cancer diagnosis and prognosis of disease development, as well as the possible beneficial effects of STAT3 targeted therapy. There is an increasing evidence STAT3 inhibitors, such as phytochemicals or synthetic compounds, may be potential therapeutics for colorectal cancer, so further research regarding the inhibitory properties of natural or synthetic compounds is justified.
- Dekker Evelien, Tanis Pieter J, Vleugels Jasper L A, Kasi Pashtoon M, Wallace Michael B. Colorectal cancer. The Lancet. 2019; 394(10207)DOI
- Ji Kun, Zhang Mingxuan, Chu Qi, Gan Yong, Ren Hui, Zhang Liyan, Wang Liwei, Li Xiaoxiu, Wang Wei. The Role of p-STAT3 as a Prognostic and Clinicopathological Marker in Colorectal Cancer: A Systematic Review and Meta-Analysis. PLOS ONE. 2016; 11(8)DOI
- Fearon Eric R., Vogelstein Bert. A genetic model for colorectal tumorigenesis. Cell. 1990; 61(5)DOI
- Wake Matthew S., Watson Christine J.. STAT3 the oncogene - still eluding therapy?. FEBS Journal. 2015; 282(14)DOI
- Laudisi Federica, Cherubini Fabio, Di Grazia Antonio, Dinallo Vincenzo, Di Fusco Davide, Franzè Eleonora, Ortenzi Angela, Salvatori Illari, Scaricamazza Silvia, Monteleone Ivan, Sakamoto Naoya, Monteleone Giovanni, Stolfi Carmine. Progranulin sustains STAT 3 hyper‐activation and oncogenic function in colorectal cancer cells. Molecular Oncology. 2019; 13(10)DOI
- Xiong Ailian, Yang Zhengduo, Shen Yicheng, Zhou Jia, Shen Qiang. Transcription Factor STAT3 as a Novel Molecular Target for Cancer Prevention. Cancers. 2014; 6(2)DOI
- Yu Hua, Lee Heehyoung, Herrmann Andreas, Buettner Ralf, Jove Richard. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nature Reviews Cancer. 2014; 14(11)DOI
- Grivennikov Sergei I., Greten Florian R., Karin Michael. Immunity, Inflammation, and Cancer. Cell. 2010; 140(6)DOI
- Shi Yin, Zhang Zhen, Qu Xintao, Zhu Xiaoxiao, Zhao Lin, Wei Ran, Guo Qiang, Sun Linlin, Yin Xunqiang, Zhang Yunhong, Li Xia. Roles of STAT3 in leukemia (Review). International Journal of Oncology. 2018. DOI
- Xin Ping, Xu Xiaoyun, Deng Chengjie, Liu Shuang, Wang Youzhi, Zhou Xuegang, Ma Hongxing, Wei Donghua, Sun Shiqin. The role of JAK/STAT signaling pathway and its inhibitors in diseases. International Immunopharmacology. 2020; 80DOI
- Pilati Camilla, Zucman-Rossi Jessica. Mutations leading to constitutive active gp130/JAK1/STAT3 pathway. Cytokine & Growth Factor Reviews. 2015; 26(5)DOI
- Bournazou Eirini, Bromberg Jacqueline. Targeting the tumor microenvironment. JAK-STAT. 2013; 2(2)DOI
- Bowman Tammy, Garcia Roy, Turkson James, Jove Richard. STATs in oncogenesis. Oncogene. 2000; 19(21)DOI
- Kim Byung-Hak, Yi Eun Hee, Ye Sang-Kyu. Signal transducer and activator of transcription 3 as a therapeutic target for cancer and the tumor microenvironment. Archives of Pharmacal Research. 2016; 39(8)DOI
- Monique C Trengove, Alister C Ward. SOCS proteins in development and disease. Am J Clin Exp Immunol. 2013; 2(1):1-29. PubMed
- Shuai Ke. Regulation of cytokine signaling pathways by PIAS proteins. Cell Research. 2006; 16(2)DOI
- Horiguchi Akio, Oya Mototsugu, Marumo Ken, Murai Masaru. STAT3, but not ERKs, mediates the IL-6–induced proliferation of renal cancer cells, ACHN and 769P. Kidney International. 2002; 61(3)DOI
- Corvinus Florian M., Orth Carina, Moriggl Richard, Tsareva Svetlana A., Wagner Stefan, Pfitzner Edith B., Baus Daniela, Kaufman Roland, Huber Lukas A., Zatloukal Kurt, Beug Hartmut, Öhlschläger Peter, Schütz Alexander, Halbhuber Karl-Jürgen, Friedrich Karlheinz. Persistent STAT3 Activation in Colon Cancer Is Associated with Enhanced Cell Proliferation and Tumor Growth. Neoplasia. 2005; 7(6)DOI
- Lin L., Liu A., Peng Z., Lin H.-J., Li P.-K., Li C., Lin J.. STAT3 Is Necessary for Proliferation and Survival in Colon Cancer-Initiating Cells. Cancer Research. 2011; 71(23)DOI
- Catlett-Falcone Robyn, Landowski Terry H, Oshiro Marc M, Turkson James, Levitzki Alexander, Savino Rocco, Ciliberto Gennaro, Moscinski Lynn, Fernández-Luna Jose Luis, Nuñez Gabriel, Dalton William S, Jove Richard. Constitutive Activation of Stat3 Signaling Confers Resistance to Apoptosis in Human U266 Myeloma Cells. Immunity. 1999; 10(1)DOI
- Epling-Burnette P.K., Liu Jin Hong, Catlett-Falcone Robyn, Turkson James, Oshiro Marc, Kothapalli Ravi, Li Yongxiang, Wang Ju-Ming, Yang-Yen Hsin-Fang, Karras James, Jove Richard, Loughran Thomas P.. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. Journal of Clinical Investigation. 2001; 107(3)DOI
- Lee Haeri, Jeong Ae Jin, Ye Sang-Kyu. Highlighted STAT3 as a potential drug target for cancer therapy. BMB Reports. 2019; 52(7)DOI
- Tang Shengbo, Yuan Xihong, Song Jintian, Chen Yigui, Tan Xiaojie, Li Qiyun. Association analyses of the JAK/STAT signaling pathway with the progression and prognosis of colon cancer. Oncology Letters. 2018. DOI
- Said Anan, Raufman Jean-Pierre, Xie Guofeng. The Role of Matrix Metalloproteinases in Colorectal Cancer. Cancers. 2014; 6(1)DOI
- Dragutinović Vesna V., Radonjić Nevena V., Petronijević Nataša D., Tatić Svetislav B., Dimitrijević Ivan B., Radovanović Nebojša S., Krivokapić Zoran V.. Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) in preoperative serum as independent prognostic markers in patients with colorectal cancer. Molecular and Cellular Biochemistry. 2011; 355(1-2)DOI
- Kryczka Jakub, Stasiak Marta, Dziki Lukasz, Mik Michał, Dziki Adam, Cierniewski Czesław S.. Matrix Metalloproteinase-2 Cleavage of the β1 Integrin Ectodomain Facilitates Colon Cancer Cell Motility. Journal of Biological Chemistry. 2012; 287(43)DOI
- Xu Zhangwei, Shi Hai, Li Qi, Mei Qiao, Bao Junjun, Shen Yuxian, Xu Jianming. Mouse macrophage metalloelastase generates angiostatin from plasminogen and suppresses tumor angiogenesis in murine colon cancer. Oncology Reports. 2008. DOI
- Yang W, Arii S, Gorrin-Rivas MJ, Mori A, Onodera H, Imamura M. Human macrophage metalloelastase gene expression in colorectal carcinoma and its clinicopathologic significance. Cancer. 2001; 91(7):1277-1283. PubMed
- Goulart André, Ferreira Carla, Rodrigues Ana, Coimbra Barbara, Sousa Nuno, Leão Pedro. The correlation between serum vascular endothelial growth factor (VEGF) and tumor VEGF receptor 3 in colorectal cancer. Annals of Surgical Treatment and Research. 2019; 97(1)DOI
- Tsai Hsiang-Lin, Yang I-Ping, Lin Chih-Hung, Chai Chee-Yin, Huang Yu-Ho, Chen Chin-Fan, Hou Ming-Feng, Kuo Chao-Hung, Juo Suh-Hang, Wang Jaw-Yuan. Predictive value of vascular endothelial growth factor overexpression in early relapse of colorectal cancer patients after curative resection. International Journal of Colorectal Disease. 2012; 28(3)DOI
- Guba Markus, Seeliger Hendrik, Kleespies Axel, Jauch Karl-Walter, Bruns Christiane. Vascular endothelial growth factor in colorectal cancer. International Journal of Colorectal Disease. 2004; 19(6)DOI
- Slattery Martha L., Lundgreen Abbie, Kadlubar Susan A., Bondurant Kristina L., Wolff Roger K.. JAK/STAT/SOCS-signaling pathway and colon and rectal cancer. Molecular Carcinogenesis. 2011; 52(2)DOI
- Inagaki-Ohara Kyoko, Kondo Taisuke, Ito Minako, Yoshimura Akihiko. SOCS, inflammation, and cancer. JAK-STAT. 2013; 2(3)DOI
- Matsumoto Satoshi, Hara Taeko, Mitsuyama Keiichi, Yamamoto Mayuko, Tsuruta Osamu, Sata Michio, Scheller Jürgen, Rose-John Stefan, Kado Sho-ichi, Takada Toshihiko. Essential Roles of IL-6Trans-Signaling in Colonic Epithelial Cells, Induced by the IL-6/Soluble–IL-6 Receptor Derived from Lamina Propria Macrophages, on the Development of Colitis-Associated Premalignant Cancer in a Murine Model. The Journal of Immunology. 2009; 184(3)DOI
- Chen Qi, Lv Jianjun, Yang Wenwen, Xu Baoping, Wang Zheng, Yu Zihao, Wu Jiawei, Yang Yang, Han Yuehu. Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis. Theranostics. 2019; 9(22)DOI
- Siveen Kodappully Sivaraman, Sikka Sakshi, Surana Rohit, Dai Xiaoyun, Zhang Jingwen, Kumar Alan Prem, Tan Benny K.H., Sethi Gautam, Bishayee Anupam. Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2014; 1845(2)DOI
- Xu Qing, Briggs Jon, Park Sungman, Niu Guilian, Kortylewski Marcin, Zhang Shumin, Gritsko Tanya, Turkson James, Kay Heidi, Semenza Gregg L, Cheng Jin Q, Jove Richard, Yu Hua. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 2005; 24(36)DOI
- Fan Xiang-Jun, Wang Yao, Wang Lei, Zhu Mingyan. Salidroside induces apoptosis and autophagy in human colorectal cancer cells through inhibition of PI3K/Akt/mTOR pathway. Oncology Reports. 2016; 36(6)DOI
- Kuan-Xue Sun, Hong-Wei Xia, Rong-Long Xia. Anticancer effect of salidroside on colon cancer through inhibiting JAK2/STAT3 signaling pathway. Int J Clin Exp Pathol. 2015; 8(1):615-621. PubMed
- Zhu Zhitu, Sun Hongzhi, Ma Guangyou, Wang Zhenghua, Li Enze, Liu Yangyang, Liu Yunpeng. Bufalin Induces Lung Cancer Cell Apoptosis via the Inhibition of PI3K/Akt Pathway. International Journal of Molecular Sciences. 2012; 13(2)DOI
- Wang Shu-Wei, Sun Yue-Ming. The IL-6/JAK/STAT3 pathway: Potential therapeutic strategies in treating colorectal cancer. International Journal of Oncology. 2014; 44(4)DOI
- Qiu Yan-yan, Hu Qiang, Tang Qing-feng, Feng Wen, Hu Song-jiao, Liang Bo, Peng Wen, Yin Pei-hao. MicroRNA-497 and bufalin act synergistically to inhibit colorectal cancer metastasis. Tumor Biology. 2013; 35(3)DOI
- Liu Xuan, Ji Qing, Ye Naijing, Sui Hua, Zhou Lihong, Zhu Huirong, Fan Zhongze, Cai Jianfeng, Li Qi. Berberine Inhibits Invasion and Metastasis of Colorectal Cancer Cells via COX-2/PGE2 Mediated JAK2/STAT3 Signaling Pathway. PLOS ONE. 2015; 10(5)DOI
- Kuo Han-Peng, Chuang Tzu-Chao, Tsai Shih-Chang, Tseng Hsiu-Hsueh, Hsu Shih-Chung, Chen Yu-Chang, Kuo Chao-Lin, Kuo Yueh-Hsiung, Liu Jah-Yao, Kao Ming-Ching. Berberine, an Isoquinoline Alkaloid, Inhibits the Metastatic Potential of Breast Cancer Cells via Akt Pathway Modulation. Journal of Agricultural and Food Chemistry. 2012; 60(38)DOI
- Hamsa T. P., Kuttan Girija. Berberine Inhibits Pulmonary Metastasis through Down-regulation of MMP in Metastatic B16F-10 Melanoma Cells. Phytotherapy Research. 2011; 26(4)DOI
- Hu Siwang, Zhao Ruochi, Liu Yahui, Chen Junzheng, Zheng Zhijian, Wang Shuangshuang. Preventive and Therapeutic Roles of Berberine in Gastrointestinal Cancers. BioMed Research International. 2019; 2019DOI
- Hallajzadeh Jamal, Maleki Dana Parisa, Mobini Moein, Asemi Zatollah, Mansournia Mohammad Ali, Sharifi Mehran, Yousefi Bahman. Targeting of oncogenic signaling pathways by berberine for treatment of colorectal cancer. Medical Oncology. 2020; 37(6)DOI
- Li Weidong, Saud Shakir M., Young Matthew R., Colburn Nancy H., Hua Baojin. Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro. Molecular and Cellular Biochemistry. 2015; 406(1-2)DOI
- Wei Ning, Li Jun, Fang Cheng, Chang Jin, Xirou Vasiliki, Syrigos Nick K., Marks Benjamin J., Chu Edward, Schmitz John C.. Targeting colon cancer with the novel STAT3 inhibitor bruceantinol. Oncogene. 2018; 38(10)DOI
- Xiong Hua, Du Wan, Zhang Yan-Jie, Hong Jie, Su Wen-Yu, Tang Jie-Ting, Wang Ying-Chao, Lu Rong, Fang Jing-Yuan. Trichostatin A, a histone deacetylase inhibitor, suppresses JAK2/STAT3 signaling via inducing the promoter-associated histone acetylation of SOCS1 and SOCS3 in human colorectal cancer cells. Molecular Carcinogenesis. 2011; 51(2)DOI
- Kashyap Dharambir, Tuli Hardeep Singh, Sharma Anil K.. Ursolic acid (UA): A metabolite with promising therapeutic potential. Life Sciences. 2016; 146DOI
- Wang W, Zhao C, Jou D, Lü J, Zhang C, Lin L, Lin J. Ursolic acid inhibits the growth of colon cancer-initiating cells by targeting STAT3. Anticancer Res. 2013; 33(10):4279-4284. PubMed
- Shan Jian-zhen, Xuan Yan-yan, Zheng Shu, Dong Qi, Zhang Su-zhan. Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway. Journal of Zhejiang University SCIENCE B. 2009; 10(9)DOI
- LIN JIUMAO, CHEN YOUQIN, WEI LIHUI, SHEN ALING, SFERRA THOMAS J., HONG ZHENFENG, PENG JUN. Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways. International Journal of Oncology. 2013; 43(4)DOI
- Aluyen Julia Khristine, Ton Quynhanh N., Tran Thuytram, Yang Alice E., Gottlieb Helmut B., Bellanger Renee A.. Resveratrol: Potential as Anticancer Agent. Journal of Dietary Supplements. 2012; 9(1)DOI
- Li Dan, Wang Gangcheng, Jin Guoguo, Yao Ke, Zhao Zhenjiang, Bie Liangyu, Guo Yongjun, Li Ning, Deng Wenying, Chen Xiaobin, Chen Beibei, Liu Yuanyuan, Luo Suxia, Guo Zhiping. Resveratrol suppresses colon cancer growth by targeting the AKT/STAT3 signaling pathway. International Journal of Molecular Medicine. 2018. DOI
- Chae Hee-Sung, Xu Rong, Won Jae-Yeon, Chin Young-Won, Yim Hyungshin. Molecular Targets of Genistein and Its Related Flavonoids to Exert Anticancer Effects. International Journal of Molecular Sciences. 2019; 20(10)DOI
- Ronis Martin J. J.. Effects of soy containing diet and isoflavones on cytochrome P450 enzyme expression and activity. Drug Metabolism Reviews. 2016; 48(3)DOI
- Shafiee Gholamreza, Saidijam Massoud, Tavilani Heidar, Ghasemkhani Neda, Khodadadi Iraj. Genistein Induces Apoptosis and Inhibits Proliferation of HT29 Colon Cancer Cells. International Journal of Molecular and Cellular Medicine. 2016; 5(3)DOI
- Tuli Hardeep Singh, Tuorkey Muobarak Jaber, Thakral Falak, Sak Katrin, Kumar Manoj, Sharma Anil Kumar, Sharma Uttam, Jain Aklank, Aggarwal Vaishali, Bishayee Anupam. Molecular Mechanisms of Action of Genistein in Cancer: Recent Advances. Frontiers in Pharmacology. 2019; 10DOI
- Devi Kasi Pandima, Rajavel Tamilselvam, Habtemariam Solomon, Nabavi Seyed Fazel, Nabavi Seyed Mohammad. Molecular mechanisms underlying anticancer effects of myricetin. Life Sciences. 2015; 142DOI
- Kumamoto Takuma, Fujii Makoto, Hou De-Xing. Myricetin directly targets JAK1 to inhibit cell transformation. Cancer Letters. 2009; 275(1)DOI
- Kim Byung-Hak, Won Cheolhee, Lee Yun-Han, Choi Jung Sook, Noh Kum Hee, Han Songhee, Lee Haeri, Lee Chang Seok, Lee Dong-Sup, Ye Sang-Kyu, Kim Myoung-Hwan. Sophoraflavanone G induces apoptosis of human cancer cells by targeting upstream signals of STATs. Biochemical Pharmacology. 2013; 86(7)DOI
- Lin Wei, Zheng Liangpu, Zhuang Qunchuan, Zhao Jinyan, Cao Zhiyun, Zeng Jianwei, Lin Shan, Xu Wei, Peng Jun. 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 Complementary and Alternative Medicine. 2013; 13(1)DOI
- Peng Jun. Pien Tze Huang inhibits tumor cell proliferation and promotes apoptosis via suppressing the STAT3 pathway in a colorectal cancer mouse model. International Journal of Oncology. 2012. DOI
- Cai Qiaoyan, Lin Jiumao, Wei Lihui, Zhang Ling, Wang Lili, Zhan Youzhi, Zeng Jianwei, Xu Wei, Shen Aling, Hong Zhenfeng, Peng Jun. Hedyotis diffusa Willd Inhibits Colorectal Cancer Growth in Vivo via Inhibition of STAT3 Signaling Pathway. International Journal of Molecular Sciences. 2012; 13(5)DOI
- Drutovic David, Chripkova Martina, Pilatova Martina, Kruzliak Peter, Perjesi Pal, Sarissky Marek, Lupi Monica, Damia Giovanna, Broggini Massimo, Mojzis Jan. Benzylidenetetralones, cyclic chalcone analogues, induce cell cycle arrest and apoptosis in HCT116 colorectal cancer cells. Tumor Biology. 2014; 35(10)DOI
- Mahapatra Debarshi Kar, Bharti Sanjay Kumar, Asati Vivek. Anti-cancer chalcones: Structural and molecular target perspectives. European Journal of Medicinal Chemistry. 2015; 98DOI
- Lin Shichong, Yang Lehe, Yao Yulei, Xu Lingyuan, Xiang Youqun, Zhao Haiyang, Wang Liangxing, Zuo Zhigui, Huang Xiaoying, Zhao Chengguang. Flubendazole demonstrates valid antitumor effects by inhibiting STAT3 and activating autophagy. Journal of Experimental & Clinical Cancer Research. 2019; 38(1)DOI
- Ye Ting-Hong, Yang Fang-Fang, Zhu Yong-Xia, Li Ya-Li, Lei Qian, Song Xue-Jiao, Xia Yong, Xiong Ying, Zhang Li-Dan, Wang Ning-Yu, Zhao Li-Feng, Gou Hong-Feng, Xie Yong-Mei, Yang Sheng-Yong, Yu Luo-Ting, Yang Li, Wei Yu-Quan. Inhibition of Stat3 signaling pathway by nifuroxazide improves antitumor immunity and impairs colorectal carcinoma metastasis. Cell Death & Disease. 2017; 8(1)DOI
- Xiong Hua, Zhang Zhi-Gang, Tian Xiao-Qing, Sun Dan-Feng, Liang Qin-Chuan, Zhang Yan-Jie, Lu Rong, Chen Ying-Xuan, Fang Jing-Yuan. Inhibition of JAK1, 2/STAT3 Signaling Induces Apoptosis, Cell Cycle Arrest, and Reduces Tumor Cell Invasion in Colorectal Cancer Cells. Neoplasia. 2008; 10(3)DOI
- Kusaba T. Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. Journal of Clinical Pathology. 2005; 58(8)DOI
- Chen L. F., Cohen E. E. W., Grandis J. R.. New Strategies in Head and Neck Cancer: Understanding Resistance to Epidermal Growth Factor Receptor Inhibitors. Clinical Cancer Research. 2010; 16(9)DOI
- Yang Joon-Yeop, Zhong Xiancai, Yum Hye-Won, Lee Hyung-Jun, Kundu Joydeb Kumar, Na Hye-Kyung, Surh Young-Joon. Curcumin Inhibits STAT3 Signaling in the Colon of Dextran Sulfate Sodium-treated Mice. Journal of Cancer Prevention. 2013; 18(2)DOI
- Chung Seyung S., Dutta Pranabananda, Chard Nathaniel, Wu Yong, Chen Qiao-Hong, Chen Guanglin, Vadgama Jaydutt. A novel curcumin analog inhibits canonical and non-canonical functions of telomerase through STAT3 and NF-κB inactivation in colorectal cancer cells. Oncotarget. 2019; 10(44)DOI
- Yang Lehe, Lin Shichong, Xu Lingyuan, Lin Jiayuh, Zhao Chengguang, Huang Xiaoying. Novel activators and small-molecule inhibitors of STAT3 in cancer. Cytokine & Growth Factor Reviews. 2019; 49DOI
- Li Chungen, Chen Caili, An Qi, Yang Tao, Sang Zitai, Yang Yang, Ju Yuan, Tong Aiping, Luo Youfu. A novel series of napabucasin derivatives as orally active inhibitors of signal transducer and activator of transcription 3 (STAT3). European Journal of Medicinal Chemistry. 2019; 162DOI
- Proia David A., Foley Kevin P., Korbut Tim, Sang Jim, Smith Don, Bates Richard C., Liu Yuan, Rosenberg Alex F., Zhou Dan, Koya Keizo, Barsoum James, Blackman Ronald K.. Multifaceted Intervention by the Hsp90 Inhibitor Ganetespib (STA-9090) in Cancer Cells with Activated JAK/STAT Signaling. PLoS ONE. 2011; 6(4)DOI
- Nagaraju Ganji Purnachandra, Park Wungki, Wen Jing, Mahaseth Hemchandra, Landry Jerome, Farris Alton B., Willingham Field, Sullivan Patrick S., Proia David A., El-Hariry Iman, Taliaferro-Smith LaTonia, Diaz Roberto, El-Rayes Bassel F.. Erratum to: Antiangiogenic effects of ganetespib in colorectal cancer mediated through inhibition of HIF-1α and STAT-3. Angiogenesis. 2013; 16(4)DOI