Signal transducer and activator of transcription 6 as a target in colon cancer therapy (Review)

Delgado‐Ramirez, Yael; Colly, Vaneesa; Gonzalez, Giovanni Villanueva; León-Cabrera, Sonia

doi:10.3892/ol.2020.11614

Cited by 16 publications

(13 citation statements)

References 65 publications

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“…Elevated levels of IL4, IL13, or their receptors have been associated with poorer patient outcomes such as cancer progression, recurrence, or reduced survival. Some examples where this is the case include but are not limited to colon cancer ( Barderas et al, 2012 ; Delgado-Ramirez et al, 2020 ), clear cell renal cell carcinoma ( Chang et al, 2015 ), bladder cancer ( Joshi et al, 2014 ), pleural mesothelioma ( Burt et al, 2012 ), ovarian cancer ( Kioi et al, 2005 ), and soft tissue sarcomas ( Kim et al, 2021 ). Type 2 immunity has already been investigated as a target for treatment.…”

Section: Type 2 Inflammatory Pathways Unveiled In Studies Of Autoimmune Tumorigenesis May Provide New Targets To Improve Cancer Immune Thmentioning

confidence: 99%

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Chen

2021

Front. Cell Dev. Biol.

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Recent epidemiological studies have found an alarming trend of increased cancer incidence in adults younger than 50 years of age and projected a substantial rise in cancer incidence over the next 10 years in this age group. This trend was exemplified in the incidence of non-cardia gastric cancer and its disproportionate impact on non-Hispanic white females under the age of 50. The trend is concurrent with the increasing incidence of autoimmune diseases in industrialized countries, suggesting a causal link between the two. While autoimmunity has been suspected to be a risk factor for some cancers, the exact mechanisms underlying the connection between autoimmunity and cancer remain unclear and are often controversial. The link has been attributed to several mediators such as immune suppression, infection, diet, environment, or, perhaps most plausibly, chronic inflammation because of its well-recognized role in tumorigenesis. In that regard, autoimmune conditions are common causes of chronic inflammation and may trigger repetitive cycles of antigen-specific cell damage, tissue regeneration, and wound healing. Illustrating the connection between autoimmune diseases and cancer are patients who have an increased risk of cancer development associated with genetically predisposed insufficiency of cytotoxic T lymphocyte-associated protein 4 (CTLA4), a prototypical immune checkpoint against autoimmunity and one of the main targets of cancer immune therapy. The tumorigenic process triggered by CTLA4 insufficiency has been shown in a mouse model to be dependent on the type 2 cytokines interleukin-4 (IL4) and interleukin-13 (IL13). In this type 2 inflammatory milieu, crosstalk with type 2 immune cells may initiate epigenetic reprogramming of epithelial cells, leading to a metaplastic differentiation and eventually malignant transformation even in the absence of classical oncogenic mutations. Those findings complement a large body of evidence for type 1, type 3, or other inflammatory mediators in inflammatory tumorigenesis. This review addresses the potential of autoimmunity as a causal factor for tumorigenesis, the underlying inflammatory mechanisms that may vary depending on host-environment variations, and implications to cancer prevention and immunotherapy.

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Section: Type 2 Inflammatory Pathways Unveiled In Studies Of Autoimmune Tumorigenesis May Provide New Targets To Improve Cancer Immune Thmentioning

confidence: 99%

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Chen

2021

Front. Cell Dev. Biol.

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“…The signal transducer and activator of transcription 6 (STAT6) is a member of the STAT family of proteins formed by seven transcription factors involved in cytokine-related signaling [ 5 ] In particular, STAT6 participates in the cellular response to interleukin- (IL-) 4 and IL-13 and it is involved in the generation of CD4+ Th2 cells [ 5 ]. Recently, STAT6 signaling has been associated with the initiation of malignant transformation and tumor establishment, and STAT6-phosphorylation has frequently been found in malignant cells that regulate several genes crucial for the immune response and proliferation [ 6 ]. The persistent activation of STAT6 has been observed in the development of prostate, breast, and colon carcinomas [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

Delgado‐Ramirez

Ocaña-Soriano

Ledesma-Soto

et al. 2021

IJMS

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Inflammation is the main driver of the tumor initiation and progression in colitis-associated colorectal cancer (CAC). Recent findings have indicated that the signal transducer and activator of transcription 6 (STAT6) plays a fundamental role in the early stages of CAC, and STAT6 knockout (STAT6−/−) mice are highly resistant to CAC development. Regulatory T (Treg) cells play a major role in coordinating immunomodulation in cancer; however, the role of STAT6 in the induction and function of Treg cells is poorly understood. To clarify the contribution of STAT6 to CAC, STAT6−/− and wild type (WT) mice were subjected to an AOM/DSS regimen, and the frequency of peripheral and local Treg cells was determined during the progression of CAC. When STAT6 was lacking, a remarkable reduction in tumor growth was observed, which was associated with decreased inflammation and an increased number of CD4+CD25+Foxp3+ cells in the colon, circulation, and spleen, including an over-expression of TGF-beta, IL-10, and Foxp3, compared to WT mice, during the early stages of CAC development. Conversely, WT mice showed an inverse frequency of Treg cells compared with STAT6−/− mice, which was followed by intestinal tumor formation. Increased mucosal inflammation, histological damage, and tumorigenesis were restored to levels observed in WT mice when an early inhibition/depletion of Treg cells was performed in STAT6−/− mice. Thus, with STAT6 deficiency, an increased number of Treg cells induce resistance against tumorigenesis, arresting tumor-promoting inflammation. We reported a direct role of STAT6 in the induction and function of Treg cells during CAC development and suggest that STAT6 is a potential target for the modulation of immune response in colitis and CAC.

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“…However, even if the key oncogenic role of NAB2–STAT6 may be related to the lack of repressive activity of NAB2 upon its targets, STAT6 dysfunction could also play an important part in SFT development. In fact, STAT6 seems to play a significant role in transcription and inflammation [ 12 , 13 ], processes linked to cancer development and progression [ 14 , 15 , 16 , 17 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

A Novel NFIX-STAT6 Gene Fusion in Solitary Fibrous Tumor: A Case Report

Moura

Díaz‐Martín

Bagué

et al. 2021

IJMS

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Solitary fibrous tumor is a rare subtype of soft-tissue sarcoma with a wide spectrum of histopathological features and clinical behaviors, ranging from mildly to highly aggressive tumors. The defining genetic driver alteration is the gene fusion NAB2–STAT6, resulting from a paracentric inversion within chromosome 12q, and involving several different exons in each gene. STAT6 (signal transducer and activator of transcription 6) nuclear immunostaining and/or the identification of NAB2–STAT6 gene fusion is required for the diagnostic confirmation of solitary fibrous tumor. In the present study, a new gene fusion consisting of Nuclear Factor I X (NFIX), mapping to 19p13.2 and STAT6, mapping to 12q13.3 was identified by targeted RNA-Seq in a 74-year-old female patient diagnosed with a deep-seated solitary fibrous tumor in the pelvis. Histopathologically, the neoplasm did not display nuclear pleomorphism or tumor necrosis and had a low proliferative index. A total of 378 unique reads spanning the NFIXexon8–STAT6exon2 breakpoint with 55 different start sites were detected in the bioinformatic analysis, which represented 59.5% of the reads intersecting the genomic location on either side of the breakpoint. Targeted RNA-Seq results were validated by RT-PCR/ Sanger sequencing. The identification of a new gene fusion partner for STAT6 in solitary fibrous tumor opens intriguing new hypotheses to refine the role of STAT6 in the sarcomatogenesis of this entity.

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Signal transducer and activator of transcription 6 as a target in colon cancer therapy (Review)

Cited by 16 publications

References 65 publications

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

A Novel NFIX-STAT6 Gene Fusion in Solitary Fibrous Tumor: A Case Report

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