The Role of STAT3 Signaling in Different Types of Cancers: A Comprehensive Review

Signal transducer and activator of transcription (STAT3) is an important transcription factor capable of mediating or even driving cancer progression through hyperactivation or gain-offunction mutations. It plays a key role in regulating host immune and inflammatory responses and in the pathogenesis of many cancers. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a vital role in tumor growth and metastasis. Hyperactive STAT3 is also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. The classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. In this review, we discuss the functions and the roles of STAT3 signal in various types of cancers.

Download Full-text

Role of STAT3 in Cancer Metastasis and Translational Advances

BioMed Research International ◽

10.1155/2013/421821 ◽

2013 ◽

Vol 2013 ◽

pp. 1-15 ◽

Cited By ~ 149

Author(s):

Mohammad Zahid Kamran ◽

Prachi Patil ◽

Rajiv P. Gude

Keyword(s):

Cancer Metastasis ◽

Cellular Proliferation ◽

Nuclear Translocation ◽

Signal Transducer ◽

Surface Receptors ◽

Physiological Conditions ◽

Stat3 Signaling ◽

Tumor Growth And Metastasis ◽

Transcription 3

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling.

Download Full-text

The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00450-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xiulin Jiang ◽

Baiyang Liu ◽

Zhi Nie ◽

Lincan Duan ◽

Qiuxia Xiong ◽

...

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Target Genes ◽

Rna Modification ◽

Biological Functions ◽

Rna Methylation ◽

Downstream Target ◽

Different Types ◽

M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

Download Full-text

The Role of Cancer-associated Fibroblasts in Tumorigenesis of Gastric Cancer

Current Pharmaceutical Design ◽

10.2174/1381612824666180601094056 ◽

2018 ◽

Vol 24 (28) ◽

pp. 3297-3302 ◽

Cited By ~ 3

Author(s):

Zhilong Ma ◽

Min Chen ◽

Xiaohu Yang ◽

Bin Xu ◽

Zhenshun Song ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Tumor Biology ◽

Vital Role ◽

Cancer Associated Fibroblasts ◽

Gastric Cancer Cells ◽

Stromal Fibroblasts ◽

Tumor Microenvironments ◽

Tumorigenesis And Progression

Cancer-associated fibroblasts (CAFs) are an important cell type present in solid tumor microenvironments, including that of gastric cancer. They play a vital role in the promotion of tumorigenesis, angiogenesis, and cancer progression through paracrine signaling and modulation of the extracellular matrix. However, the exact molecular mechanism underlying the interaction between gastric cancer cells and stromal fibroblasts remains poorly understood. Recent studies have demonstrated that various factors, such as gene and microRNA variations, are involved in this process. This review discusses recent advances in understanding how these factors are regulated in CAFs and how they affect tumor biology, which may improve our understanding of their role in gastric cancer tumorigenesis and progression and provide new promising targets for therapeutic strategies.

Download Full-text

How Antimalarials and Antineoplastic Drugs can Interact in Combination Therapies: a Perspective on the Role of PPT1 Enzyme

Current Drug Metabolism ◽

10.2174/1389200222666211118114057 ◽

2021 ◽

Vol 22 ◽

Author(s):

Diana Duarte ◽

Nuno Vale

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Antineoplastic Agents ◽

Antimalarial Drugs ◽

Antineoplastic Drugs ◽

Anticancer Effects ◽

Different Types ◽

Important Pathway ◽

Palmitoyl Protein Thioesterase

: Antimalarial drugs from different classes have demonstrated anticancer effects in different types of cancer cells, but their complete mode of action in cancer remains unknown. Recently, several studies reported the important role of palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme, as the molecular target of chloroquine and its derivates in cancer. It was also found that PPT1 is overexpressed in different types of cancer, such as breast, colon, etc. Our group has found a synergistic interaction between antimalarial drugs, such as mefloquine, artesunate and chloroquine and antineoplastic drugs in breast cancer cells, but the mechanism of action was not determined. Here, we describe the importance of autophagy and lysosomal inhibitors in tumorigenesis and hypothesize that other antimalarial agents besides chloroquine could also interact with PPT1 and inhibit the mechanistic target of rapamycin (mTOR) signalling, an important pathway in cancer progression. We believe that PPT1 inhibition results in changes in the lysosomal metabolism that result in less accumulation of antineoplastic drugs in lysosomes, which increases the bioavailability of the antineoplastic agents. Taken together, these mechanisms help to explain the synergism of antimalarial and antineoplastic agents in cancer cells.

Download Full-text

The Role of Tumor-Associated Macrophages in Leukemia

Acta Haematologica ◽

10.1159/000500315 ◽

2019 ◽

Vol 143 (2) ◽

pp. 112-117 ◽

Cited By ~ 2

Author(s):

Yueyang Li ◽

M. James You ◽

Yaling Yang ◽

Dongzhi Hu ◽

Chen Tian

Keyword(s):

Stem Cells ◽

Innate Immunity ◽

Mesenchymal Stem Cells ◽

Immune Cells ◽

Leukemia Cell ◽

Tumor Associated Macrophages ◽

Intrinsic Factors ◽

Different Types ◽

Tumor Growth And Metastasis

In addition to intrinsic factors, leukemia cell growth is influenced by the surrounding nonhematopoietic cells in the leukemic microenvironment, including fibroblasts, mesenchymal stem cells, vascular cells, and various immune cells. Despite the fact that macrophages are an important component of human innate immunity, tumor-associated macrophages (TAMs) have long been considered as an accomplice promoting tumor growth and metastasis. TAMs are activated by an abnormal malignant microenvironment, polarizing into a specific phenotype and participating in tumor progression. TAMs that exist in the microenvironment of different types of leukemia are called leukemia-associated macrophages (LAMs), which are reported to be associated with the progression of leukemia. This review describes the role of LAMs in different leukemia subtypes.

Download Full-text

Extracellular Vesicles-Mediated Transfer of miRNA Let-7b from PC3 Cells to Macrophages

Genes ◽

10.3390/genes11121495 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1495

Author(s):

Egidia Costanzi ◽

Rita Romani ◽

Paolo Scarpelli ◽

Ilaria Bellezza

Keyword(s):

Prostate Cancer ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Inflammatory Responses ◽

Target Cells ◽

Prostate Cell ◽

Prostate Cancer Therapy ◽

Reverse Transcription Quantitative Pcr ◽

Pc3 Cells

Prostate-derived extracellular vesicles (pEVs) may represent a way to selectively transport cargo molecules from the producing cells to the target cells to allow biological events, both in physiological and pathological circumstances. pEVs cargo participates in the modulation of the inflammatory responses in physiological conditions and during cancer progression. In the present study, we examined the expression levels of miRNA Let-7b, in both precursor and mature forms, in noncancerous and cancerous prostate cell lines, PNT2 and PC3 respectively, and in their extracellular vesicles (EVs) using reverse-transcription quantitative PCR strategies. We showed that miRNA Let-7b was highly expressed in noncancerous cells and strongly decreased in cancerous PC3 cells, while the opposite was observed in the respective EVs, thus supporting the tumor suppressor role of miRNA Let7-b. We also demonstrated that miRNA Let-7b can be transferred to THP-1 cells via EVs, which are known to induce TAM-like polarization. Our results support the view that miRNA Let-7 b, contained in PC3-derived EVs, is associated with the increase in the miRNA Let7-b observed in TAM-like macrophages. Overall, our results indicate that circulating EV-loaded miRNA might be useful biomarkers for prostate cancer progression and might also support a possible use of pEVs as targets for prostate cancer therapy.

Download Full-text

The Role of TRPC1 in Modulating Cancer Progression

Cells ◽

10.3390/cells9020388 ◽

2020 ◽

Vol 9 (2) ◽

pp. 388 ◽

Cited By ~ 4

Author(s):

Osama M Elzamzamy ◽

Reinhold Penner ◽

Lori A Hazlehurst

Keyword(s):

Cancer Progression ◽

Calcium Ions ◽

Functional Role ◽

Second Messengers ◽

Metastatic Tumor ◽

Unique Role ◽

Promising Target ◽

Tumor Growth And Metastasis ◽

Cancer Multiple

Calcium ions (Ca2+) play an important role as second messengers in regulating a plethora of physiological and pathological processes, including the progression of cancer. Several selective and non-selective Ca2+-permeable ion channels are implicated in mediating Ca2+ signaling in cancer cells. In this review, we are focusing on TRPC1, a member of the TRP protein superfamily and a potential modulator of store-operated Ca2+ entry (SOCE) pathways. While TRPC1 is ubiquitously expressed in most tissues, its dysregulated activity may contribute to the hallmarks of various types of cancers, including breast cancer, pancreatic cancer, glioblastoma multiforme, lung cancer, hepatic cancer, multiple myeloma, and thyroid cancer. A range of pharmacological and genetic tools have been developed to address the functional role of TRPC1 in cancer. Interestingly, the unique role of TRPC1 has elevated this channel as a promising target for modulation both in terms of pharmacological inhibition leading to suppression of tumor growth and metastasis, as well as for agonistic strategies eliciting Ca2+ overload and cell death in aggressive metastatic tumor cells.

Download Full-text

N-cadherin antagonists as oncology therapeutics

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2014.0039 ◽

2015 ◽

Vol 370 (1661) ◽

pp. 20140039 ◽

Cited By ~ 20

Author(s):

Orest W. Blaschuk

Keyword(s):

Cell Adhesion ◽

Cancer Progression ◽

Structural Integrity ◽

Cancer Therapies ◽

Transmembrane Glycoprotein ◽

Anti Cancer ◽

Different Types ◽

Poorly Differentiated ◽

Novel Strategy

The cell adhesion molecule (CAM), N-cadherin, has emerged as an important oncology therapeutic target. N-cadherin is a transmembrane glycoprotein mediating the formation and structural integrity of blood vessels. Its expression has also been documented in numerous types of poorly differentiated tumours. This CAM is involved in regulating the proliferation, survival, invasiveness and metastasis of cancer cells. Disruption of N-cadherin homophilic intercellular interactions using peptide or small molecule antagonists is a promising novel strategy for anti-cancer therapies. This review discusses: the discovery of N-cadherin, the mechanism by which N-cadherin promotes cell adhesion, the role of N-cadherin in blood vessel formation and maintenance, participation of N-cadherin in cancer progression, the different types of N-cadherin antagonists and the use of N-cadherin antagonists as anti-cancer drugs.

Download Full-text

Novel role of STAT3 in microglia-dependent neuroinflammation after experimental subarachnoid haemorrhage

Stroke and Vascular Neurology ◽

10.1136/svn-2021-001028 ◽

2021 ◽

pp. svn-2021-001028

Author(s):

Zhiyuan Vera Zheng ◽

Junfan Chen ◽

Hao Lyu ◽

Sin Yu Erica Lam ◽

Gang Lu ◽

...

Keyword(s):

Subarachnoid Haemorrhage ◽

Inflammatory Responses ◽

Morphological Changes ◽

Neuronal Loss ◽

Signalling Pathway ◽

Janus Kinase ◽

Signal Transducer ◽

Experimental Subarachnoid Haemorrhage ◽

Stat3 Signalling

Background and purposeSignal transducer and activator of transcription 3 (STAT3) may contribute to the proinflammation in the central nervous system diseases by modulating the microglial responses. Thus, this study was intended to investigate the effect of STAT3 on microglia-dependent neuroinflammation and functional outcome after experimental subarachnoid haemorrhage (SAH).MethodsThe SAH model was established by endovascular perforation in the mouse. Real-time PCR (RtPCR) and western blot were used to examine the dynamic STAT3 signalling pathway responses after SAH. To clarify the role of the STAT3 signalling pathway in the microglia-dependent neuroinflammation after SAH, the microglia-specific STAT3 knockout (KO) mice were generated by the Cre-LoxP system. The neurological functions were assessed by Catwalk and Morris water maze tests. Neuronal loss after SAH was determined by immunohistochemistry staining. Microglial polarisation status after STAT3 KO was then examined by RtPCR and immunofluorescence.ResultsThe STAT3 and Janus kinase-signal transducer 2 activated immediately with the upregulation and phosphorylation after SAH. Downstream factors and related mediators altered dynamically and accordingly. Microglial STAT3 deletion ameliorated the neurological impairment and alleviated the early neuronal loss after SAH. To investigate the underlying mechanism, we examined the microglial reaction after STAT3 KO. STAT3 deletion reversed the increase of microglia after SAH. Loss of STAT3 triggered the early morphological changes of microglia and primed microglia from M1 to M2 polarisation. Functionally, microglial STAT3 deletion suppressed the SAH-induced proinflammation and promoted the anti-inflammation in the early phase.ConclusionsSTAT3 is closely related to the microglial polarisation transition and modulation of microglia-dependent neuroinflammation. Microglial STAT3 deletion improved neurological function and neuronal survival probably through promoting M2 polarisation and anti-inflammatory responses after SAH. STAT3 may serve as a promising therapeutic target to alleviate early brain injury after SAH.

Download Full-text

Nerves in the Tumor Microenvironment: Origin and Effects

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.601738 ◽

2020 ◽

Vol 8 ◽

Author(s):

Wenjun Wang ◽

Lingyu Li ◽

Naifei Chen ◽

Chao Niu ◽

Zhi Li ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Progression ◽

Perineural Invasion ◽

Vital Role ◽

Cancer Growth ◽

Alternative Route ◽

Sympathetic Nervous ◽

Molecular Bases

Studies have reported the vital role of nerves in tumorigenesis and cancer progression. Nerves infiltrate the tumor microenvironment thereby enhancing cancer growth and metastasis. Perineural invasion, a process by which cancer cells invade the surrounding nerves, provides an alternative route for metastasis and generation of tumor-related pain. Moreover, central and sympathetic nervous system dysfunctions and psychological stress-induced hormone network disorders may influence the malignant progression of cancer through multiple mechanisms. This reciprocal interaction between nerves and cancer cells provides novel insights into the cellular and molecular bases of tumorigenesis. In addition, they point to the potential utility of anti-neurogenic therapies. This review describes the evolving cross-talk between nerves and cancer cells, thus uncovers potential therapeutic targets for cancer.

Download Full-text