STAT3 in Colorectal Cancer

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1		Antonios N. Gargalionis	+ 2307 word(s)	2307	2021-08-18 04:42:14	\|
2	The format is correct	Lindsay Dong	Meta information modification	2307	2021-09-28 08:25:17	\|

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9081016

Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor that has been firmly associated with colorectal cancer (CRC) initiation and development. STAT3 mediates key inflammatory mechanisms in colitis-associated cancer, becomes excessively activated in CRC, and enhances cancer cell proliferation, tumor growth, angiogenesis, invasion, and migration. STAT3 hyperactivation in malignant cells, surrounding immune cells and cancer-associated fibroblasts, mediates inhibition of the innate and adaptive immunity of the tumor microenvironment, and, therefore, tumor evasion from the immune system.

STAT3 colorectal cancer colorectal cancer inflammation colorectal cancer immunotherapy colorectal cancer resistance

1. Introduction

Colorectal cancer (CRC) represents one of the leading types of malignancy, in both genders, worldwide. Several risk factors have been acknowledged, such as increasing age and positive family history (hereditary CRC syndrome accounts for 5–7% of the patients), as well as lifestyle factors, featuring obesity, smoking, and increased intake of alcohol and red/processed meat ^[1]. Most CRCs initiate from cancer stem cells (CSC)s inside the colonic epithelium, accumulating progressive genetic and epigenetic alterations. These alterations lead to impaired gene expression and/or function, therefore favoring the activation of oncogenes and the downregulation of tumor suppressor genes ^[2].

Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family of cytoplasmic TFs, and is also the family member that has been most associated with CRC initiation and development ^[3]. STAT3 is the point of integration for various tumorigenic signaling pathways and regulates the immune response against tumors. Notably, STAT3 depicts a unique feature in CRC, as the interleukin-6 (IL-6)/STAT3 signaling axis represents a key inflammatory mechanism in colitis-associated cancer (CAC) ^[4]. STAT3 is also abundantly activated in CRC and enhances cancer cell proliferation, tumor growth, invasion, and migration ^[5]. These features highlight STAT3 as a promising therapeutic target; however, the mechanisms underlying these features have not been fully elucidated yet, in order for STAT3 inhibitors to reach the clinic ^[6].

2. STAT3 Structure and Regulation of Activity in Normal Cells and Disease

The STAT family consists of the following seven structurally and functionally associated proteins: STAT1, STAT2, STAT3, STAT4, STAT5a and STAT5b, and STAT6. STATs function as cytoplasmic signal transducers and regulators of gene transcription in the nucleus. These molecular events occur following cytokine and growth factor stimuli, and they are critical for the regulation of innate and acquired host immune responses ^[7]^[8].

STAT3 was firstly identified as a component of IL-6 signaling, which co-immunoprecipitates as a phosphoprotein in a complex with acute phase response factor (APRF) in HepG2 hepatoma cells ^[9]. It is an 88-kDa protein that harbors a conserved Src homology 2 (SH2) domain within its primary amino acid sequence ^[10]. Cytokines bind to classic cytokine receptors (e.g., IL-10), and membrane-bound and soluble receptors (e.g. IL-6, IL-11, and IL-23). Growth factors bind to their respective growth factor receptors, and peptide hormones bind to their respective G-protein-coupled receptors (GPCR)s (Figure 1) ^[10]^[11]. Upon ligand binding, the receptors mainly activate the Janus kinase (JAK) family of kinases, which trans-phosphorylate each other. JAKs further phosphorylate the C-terminus of the receptor subunit. The latter event attracts STAT3, with its SH2 domain, to a related docking site in the cytoplasmic tail of the activated receptor subunit. This leads to STAT3 phosphorylation on the Y705 tyrosine residue.

Figure 1. STAT3 signaling in colorectal cancer cells. Upon ligand binding, receptor tyrosine kinases (RTK), cytokine receptors and G-protein-coupled receptors (GPCR) lead to Janus kinase (JAK) recruitment, which facilitates signal transducer and activator of transcription-3 (STAT3) phosphorylation and homodimerization. STAT3 homodimers enter the nucleus and enhance gene transcription to induce colorectal cancer cell-specific properties. Regulation of STAT3 is achieved by non-receptor tyrosine kinases (Src, Abl), histone acetyltransferases (HAT), tyrosine phosphatases and E3 SUMO-protein ligase (PIAS3). Epidermal growth factor receptor (EGFR); extracellular matrix (ECM); fibroblast growth factor receptor (FGFR); granulocyte colony-stimulating factor receptor (GCSFR); platelet-derived growth factor receptor (PDGFR); suppressor of cytokine signaling 3 (SOCS3).

STAT3 is also phosphorylated by other intracellular kinases, such as the non-receptor tyrosine kinases Src and Abl. STAT3 phosphorylation leads to its homodimerization. The homodimer enters the nucleus, in order to exert its transcriptional activity regarding genes with diverse biological consequences ^[11]. STAT3 acetylation, by histone acetyltransferase on a lysine residue (K685), is an alternative mechanism of STAT3 activation that stabilizes the STAT3 dimer ^[12]. On the other hand, STAT3 negative regulation is mainly controlled by tyrosine phosphatases, which dephosphorylate/deactivate STAT3. STAT3 is inhibited by a suppressor of cytokine signaling 3 (SOCS3) at the receptor level, and by E3 SUMO-protein ligase (PIAS3) at the transcriptional level (Figure 1) ^[12]^[13]^[14]^[15]^[16].

3. Mechanisms of STAT3 Implication in Tumorigenesis

The canonical STAT3 pathway that functions transiently and is strictly regulated in normal cells, has been documented to be persistently activated in a variety of solid and hematological malignancies ^[17]. STAT3 is also activated by non-canonical pathways in tumorigenesis, which involve STAT3 phosphorylation in a (Ser)727 alternative site of the C-terminus, by mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), or protein kinase C (PKC) pathways. Constitutively activated STAT3 translocates to the nucleus and enhances gene transcription, which favors cell proliferation, resistance to apoptosis, survival, angiogenesis, tumor-promoting inflammation, tumor-mediated immune evasion, and, ultimately, invasion and metastasis. Recent evidence demonstrates that STAT3 promotes tumorigenesis through additional processes, including inflammation-promoting carcinogenesis, obesity and/or metabolism, CSCs, and pre-metastatic niche formation ^[18].

Aberrant STAT3 activation is mainly attributed to the excessive production of cytokines and growth factors in the tumor microenvironment (TM), high expression of protein tyrosine kinases, and epigenetic suppression of negative regulators of STAT3, such as SOCS3 and protein tyrosine phosphatases ^[19]. Particularly, the activation of the IL-6/JAK/STAT3 core axis is observed in many types of cancer. IL-6 is overexpressed in the TM and stimulates the JAK/STAT3 pathway, which is a molecular event that is associated with poor prognosis for cancer patients. JAK2 is specifically activated in myeloproliferative disorders and activates STAT3 ^[20]. IL-6 plays a protective role for cancer cells, against DNA damage, apoptosis, and oxidative stress ^[21]. Regarding angiogenesis, STAT3 is activated in cancer cells by reactive oxygen species (ROS), mechanistic target of rapamycin complex 1 (mTORC1) and/or IL-6, and further induces hypoxia-inducible factor 1-alpha (HIF-1a) activation during hypoxia. HIF-1a induces the transcription of vascular endothelial growth factor (VEGF), which, in turn, affects the surrounding endothelial cells. This event activates, once again, STAT3 via the VEGF receptor (VEGFR). In endothelial cells, STAT3, along with HIF-1a and sp1, promotes the transcription of genes that mediate the cell growth, survival, and migration of endothelial cells, therefore promoting angiogenesis ^[22].

4. Mechanisms of STAT3 Engagement in Colorectal Tumorigenesis

4.1. STAT3 Expression and Regulation in Colorectal Cancer Cells

The immunohistochemical evaluation of p-STAT3 in 108 CRC cases demonstrated cytoplasmic and nuclear expression, positive correlation of pSTAT3 expression, with the depth of the tumor invasion, Dukes, TNM stage, and reduced overall survival ^[23]. STAT3-enhanced activation in CRC occurs from IL-6 in the serum and the tumor microenvironment, from growth factors and growth factor receptors, tyrosine kinases (Src, Bcr-Abl), and loss-of-function mutations for the STAT3 suppressors/inhibitors (phosphatases, SOCS, PIAS) ^[20].

Beyond direct STAT3 regulation by upstream molecules, STAT3 is also activated by the suppression of STAT3 negative regulators, such as PTPRT ^[24]. PTPRT functions as a tumor suppressor gene, and is mutated in colon, lung, stomach, and skin (melanoma) cancers. In CRC, it is the most frequently mutated tyrosine phosphatase among the tyrosine phosphatome that was examined in 18 CRCs. PTPRT presents five mutations that decrease its activity ^[25]^[26]. STAT3 has been identified as a substrate of PTPRT. The epigenetic suppression (promoter hypermethylation) of PTPRT occurs in several human cancers, but most notably in CRC (78.7%, 289/367 tumors analyzed) ^[27].

4.2. STAT3 in Invasion and Metastasis

STAT3 is implicated in the invasion and metastasis of CRC cells, through various mechanisms. In CRC cells, the IL-6/STAT3 axis promotes EMT and, therefore, the CRC aggressive phenotype via the STAT3-dependent transcriptional upregulation of Fos-related antigen-1 (Fra-1) TF. Fra-1 belongs to the Fos family of TFs, and is associated with phenotype invasive transformation and EMT in various types of cancer. In a 229 CRC patient cohort, Fra-1 expression was positively correlated with an increased depth of invasion, lymph node, and liver metastases. Fra-1 was also expressed according to IL-6 and pSTAT3 expression. In CRC cells, STAT3 needs to be both phosphorylated and acetylated to bind to the Fra-1 promoter and induce Fra-1 transcription ^[28].

MiR-34 is known to suppress EMT. The MiR-34 gene is a target of activated STAT3, which causes transcriptional repression of miR-34, and therefore induces EMT promotion in CRC cells and tumors ^[29]. Furthermore, the p53-inducible miR-34a control of the tyrosine kinase colony-stimulating factor 1 receptor is alleviated in CRC, through a feedback loop that is mediated by STAT3 ^[30]. STAT3 is also involved by enhancing the acquisition of EMT and cancer stem cells traits by CRC cells, through transcriptional induction of NANOG TF.

4.3. STAT3 in Angiogenesis

During hypoxia, STAT3 is activated in cancer cells by ROS, mTORC1, and/or IL-6, and further induces HIF-1a. This transcription factor induces the transcription of VEGF. This event affects the surrounding endothelial cells, in order to activate, once again, STAT3 via VEGFR. In endothelial cells, STAT3, along with HIF-1a and sp1, promotes the transcription of genes that mediate cell growth, survival, and migration of ECS, therefore angiogenesis ^[22]. Corticotrophin-releasing hormone (CRH) and its receptor CRHR contribute to CRC cells proliferation, and promote angiogenesis.

4.4. STAT3 in Tumor-Promoting Inflammation

Chronic inflammation is involved in several processes during tumorigenesis, such as proliferation, survival, transformation, invasion, angiogenesis, and metastasis ^[31]. Regarding CRC, in particular, patients with inflammatory bowel diseases (ulcerative colitis—Crohn’s disease) have increased risk of developing CRC, and colitis-associated CRC (CAC) presents poor prognosis ^[31]^[32]. Studies that have employed gain-of-function and loss-of-function in vivo models show that STAT3 mediates the impact of IL-6 and IL-11 on the initiation and development of CAC. STAT3 activity is considerably reduced in the colon and intestinal epithelial cells of IL-6^-/- mice, whereas STAT3 silencing in intestinal epithelial cells has a profound effect on CRC tumorigenesis in vivo ^[4]. IL-6 and IL-11 activate STAT3 through gp130, thus establishing an IL-6, IL-11/gp130/STAT3 signaling axis that prevents enterocytes from apoptosis, and facilitates cell survival and cell proliferation, ultimately promoting tumor growth ^[33].

STAT3 is a critical regulator of inflammatory processes. Therefore, it has also emerged as key molecule for inflammation-associated processes, during tumor development of both CAC and sporadic CRC ^[34]. STAT3 is a core mediator of CAC, since it facilitates IL-6-induced proliferating and anti-apoptotic effects on intestinal epithelial cells ^[4]. Furthermore, the status of the gut microbiome and the proportion of certain gut microbiota are also important during inflammation-associated CRC, with certain bacteria either promoting or suppressing tumorigenesis ^[35]^[36]. Therefore, the abundance of Streptococcus bovis/gallolyticus, enterotoxigenic Bacteroides fragilis, and Escherichia coli NC101 have been suggested as risk factors for CRC ^[37].

5. STAT3 in Colorectal Cancer Treatment

We already know that STAT3 inhibition in vitro suppresses tumor growth and promotes apoptosis in cancer cells. STAT3 integrates the oncogenic signaling of multiple upstream kinase molecules. Therefore, STAT3 inhibition is a promising therapeutic strategy that could abrogate the oncogenic impact of several upstream activated kinase molecules. Although JAK1/2 inhibition has favorable effects in JAK/STAT-driven hematological malignancies, agents that target STAT3 are still in the early phases of development. Strategies targeting STAT3 are categorized into the following groups: (1) inhibitors of the SH2 domain or STAT3 dimerization, (2) upstream tyrosine kinase inhibitors, (3) STAT3 pathway oligonucleotides, (4) inhibitors of STAT3–DNA binding, and (5) mimics of STAT3 negative regulators ^[17]. There is a number of STAT3 inhibitors with promising efficacy in preclinical studies, which have entered clinical trials (Table 1) ^[6].

Table 1. Clinical trials of CRC patients including STAT3 inhibitors (https://clinicaltrials.gov).

Identifier	Status	Title	Condition	Phase	Drug
NCT03647839	Active, not recruiting	Modulation Of The Tumour Microenvironment Using Either Vascular Disrupting Agents or STAT3 Inhibition in Order to Synergise With PD1 Inhibition in Microsatellite Stable, Refractory Colorectal Cancer	Colorectal Cancer Metastatic	II	BBI608
NCT02983578	Active, not recruiting	Danvatirsen and Durvalumab in Treating Patients With Advanced and Refractory Pancreatic, non-small cell Lung Cancer, and Mismatch Repair Deficient Colorectal Cancer	Advanced Colorectal Carcinoma Mismatch Repair Deficiency Refractory Colorectal Carcinoma Stage III Colorectal Cancer AJCC v8 Stage IIIA Colorectal Cancer AJCC v8 Stage IIIB Colorectal Cancer AJCC v8 Stage IIIC Colorectal Cancer AJCC v8 Stage IV Colorectal Cancer AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8	II	Danvatirsen
NCT03195699	Recruiting	Oral STAT3 Inhibitor, TTI-101, in Patients With Advanced Cancers	Colorectal Cancer Advanced Cancer	I	TTI-101
NCT03522649	Recruiting	A Phase III Clinical Study of Napabucasin (GB201) Plus FOLFIRI in Adult Patients With Metastatic Colorectal Cancer	Previously Treated Metastatic Colorectal Cancer	III	BBI608
NCT02753127	Completed	A Study of Napabucasin (BBI-608) in Combination With FOLFIRI in Adult Patients With Previously Treated Metastatic Colorectal Cancer (CanStem303C)	Colorectal cancer	III	BBI608
NCT01776307	Completed	A Study of BBI608 in Adult Patients With Advanced Colorectal Cancer	Colorectal Cancer	II	BBI608
NCT03522649	Recruiting	A Phase III Clinical Study of Napabucasin (GB201) Plus FOLFIRI in Adult Patients With Metastatic Colorectal Cancer	Previously Treated Metastatic Colorectal Cancer	III	BBI608
NCT02641873	Completed	A Study of BBI608 Administrated With FOLFIRI + Bevacizumab in Adult Patients With Metastatic Colorectal Cancer	Metastatic Colorectal Cancer	I	BBI608
NCT03647839	Active, not recruiting	Modulation Of The Tumour Microenvironment Using Either Vascular Disrupting Agents or STAT3 Inhibition in Order to Synergise With PD1 Inhibition in Microsatellite Stable, Refractory Colorectal Cancer (MODULATE)	Colorectal Cancer Metastatic	II	BBI608
NCT01830621	Completed	BBI608 and Best Supportive Care vs. Placebo and Best Supportive Care in Pretreated Advanced Colorectal Carcinoma	Colorectal Carcinoma	III	BBI608

6. Conclusions

STAT3 has been established as a critical regulator of context-dependent processes in cancer cells and their surrounding stromal cells. Although there are findings that attribute STAT3 either an oncogenic or a tumor-suppressive role in solid tumors and CRC, it has been widely accepted that STAT3 activity mainly lies on STAT3 homodimerization and activation for gene transcription, which regulates proliferation, apoptosis, invasion and metastasis, angiogenesis, and TM immune status in CRC. Therefore, STAT3 inhibition is a promising therapeutic strategy, with a footnote regarding proper context-dependent application.

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