Transforming Growth Factor β Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2

Miranda, Noel F C C de; Dinther, Maarten van; Akker, Brendy E.W.M. van den; Wezel, Tom van; Dijke, Peter ten; Morreau, Hans

doi:10.1053/j.gastro.2015.02.052

Cited by 58 publications

(47 citation statements)

References 43 publications

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“…TβRII and ACVR2A, another TGF-β component, were found to be the most frequently mutated genes in MSI-H CRC from patients with Lynch syndrome [74]. A recently published paper has shown that TGF-β signaling may still remain active in some MSI-H CRC cells despite the presence of frameshift mutations in the TβRII gene [75]. The exact mechanism of the contribution of TβRII mutations to CRC is still not known.…”

Section: Tgf-β In Colorectal Cancermentioning

confidence: 99%

TGF-β signaling in liver and gastrointestinal cancers

Katz

Likhter

Jogunoori³

et al. 2016

Cancer Letters

114

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Transforming Growth Factor-β (TGF- β) plays crucial and complex roles in liver and gastrointestinal cancers. These include a multitude of distinct functions, such as maintaining stem cell homeostasis, promoting fibrosis, immune modulating, as a tumor suppressor and paradoxically, as a tumor progressor. However, key mechanisms for the switches responsible for these distinct actions are poorly understood, and remain a challenge. The Cancer Genome Atlas (TCGA) analyses and genetically engineered mouse models now provide an integrated approach to dissect these multifaceted and context-dependent driving roles of the TGF-β pathway. In this review, we will discuss the molecular mechanisms of TGF-β signaling, focusing on colorectal, gastric, pancreatic, and liver cancers. Novel drugs targeting the TGF-β pathway have been developed over the last decade, and some have proven effective in clinical trials. A better understanding of the TGF-β pathway may improve our ability to target it, thus providing more tools to the armamentarium against these deadly cancers.

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Section: Tgf-β In Colorectal Cancermentioning

confidence: 99%

TGF-β signaling in liver and gastrointestinal cancers

Katz

Likhter

Jogunoori³

et al. 2016

Cancer Letters

114

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“…TGFβR2 binds to TGFβ, which may further phosphorylate proteins, and then enters the nucleus to regulate the gene transcription (18). Mutations in TGFβR2 have been implicated in human cancer (19,20). A study by Zhang et al (21) reported that mRNA and protein expression levels of TGFβR2 were significantly lower in NPC tissues compared with the non-cancerous tissues, and EBV encoded small RNA hybridization signals in NPC demonstrated significant associations with TGFβR2 (21).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-19a promotes nasopharyngeal carcinoma by targeting transforming growth factor β receptor 2

Wang

et al. 2017

Experimental and Therapeutic Medicine

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MicroRNA (miR), a class of small non-coding RNA, function as key regulators in gene expression through directly binding to the 3′ untranslated region of their target mRNA, which further leads to translational repression or mRNA degradation. miR-19a, a member of miR-17-92 cluster, has an oncogenic role in a variety of malignant tumors. However, the exact role of miR-19a in nasopharyngeal carcinoma (NPC) has not previously been studied. The present study aimed to investigate the function and mechanism of miR-19a in regulating the viability and invasion of NPC cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) data indicated that the expression levels of miR-17-92 cluster members (miR-17, miR-18a, miR-19a and miR-20a) were frequently increased in NPC tissues compared to the normal tissues. It was also demonstrated that miR-19a was significantly upregulated in NPC C666-1 cells compared to NP69 cells (P<0.01). Knockdown of miR-19a led to a significant decrease in the viability and invasion of NPC C666-1 cells (P<0.01), and induced increased protein expression levels of transforming growth factor β receptor 2 (TGFβR2), which was further identified as a direct target gene of miR-19a by using a luciferase reporter assay. Overexpression of TGFβR2 also suppressed the viability and invasion of C666-1 cells, similar to the effects of miR-19a inhibition. Furthermore, knockdown of TGFβR2 reversed the suppressive effects of miR-19a inhibition on C666-1 cell viability and invasion, suggesting that the role of miR-19a in mediating cell viability and invasion is through directly targeting TGFβR2 in NPC cells. In addition, RT-qPCR data demonstrated that the mRNA expression level of TGFβR2 was markedly reduced in NPC tissues and C666-1 cells. In summary, the present study demonstrated an oncogenic role of miR-19a in NPC via mediation of TGFβR2. Therefore, miR-19a may be a potential therapeutic target for NPC.

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“…Loss of TGFBR2 expression enables cancer cells to escape the growth inhibitory effect of TGF-β and may cause loss of cell growth regulation. Several studies have discussed the potential mechanisms of the dysregulation of TGFBR2 [22, 23]. However, other latent mechanisms require further exploration for the clarification of the specific functions of TGFBR2 in carcinogenesis and cancer progression.…”

Section: Introductionmentioning

confidence: 99%

MiR-17-5p regulates cell proliferation and migration by targeting transforming growth factor-β receptor 2 in gastric cancer

Zhang

Duan

et al. 2016

Oncotarget

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TGFBR2 serves as an initial regulator of the TGF-β signaling pathway, and loss or reduction of its expression leads to uncontrolled cell growth and invasion. TGFBR2 plays a crucial role in the carcinogenesis and malignant process of gastric cancer, but the mechanism remains unclear. In this study, we found that TGFBR2 protein levels were consistently upregulated in gastric cancer tissues, whereas TGFBR2 mRNA levels varied among these tissues, indicating that a post-transcriptional mechanism is involved in the regulation of TGFBR2. MiRNAs are known to regulate gene expression at the post-transcriptional level. Therefore, we performed bioinformatics analyses to search for miRNAs potentially targeting TGFBR2. MiR-17-5p was found to bind to the 3′UTR of TGFBR2 mRNA, and further validation of this specific binding was performed through a reporter assay. An inverse correlation between miR-17-5p and TGFBR2 protein was observed in gastric cancer tissues. Cell studies revealed that miR-17-5p negatively regulated TGFBR2 expression by directly binding to the 3′UTR of TGFBR2 mRNA, thereby promoting cell growth and migration. We also validated the role of TGFBR2 using siRNA and an overexpression plasmid. The results of our study suggest a novel regulatory network in gastric cancer mediated by miR-17-5p and TGFBR2 and may indicate that TGFBR2 could serve as a new therapeutic target in gastric cancer.

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Transforming Growth Factor β Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2

Cited by 58 publications

References 43 publications

TGF-β signaling in liver and gastrointestinal cancers

TGF-β signaling in liver and gastrointestinal cancers

MicroRNA-19a promotes nasopharyngeal carcinoma by targeting transforming growth factor β receptor 2

MiR-17-5p regulates cell proliferation and migration by targeting transforming growth factor-β receptor 2 in gastric cancer

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