SMAD3 inducing the transcription of  STYK1 to promote the EMT process and improve the tolerance of ovarian carcinoma cells to paclitaxel

Shi, Yangyang; Zhang, Jing; Liu, Mengran; Huang, Yan; Yin, Ling

doi:10.1002/jcb.28371

Cited by 14 publications

(9 citation statements)

References 54 publications

(113 reference statements)

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“…Apart from TGFβ, other ligands can activate the TGFβ pathway, such as BMP9, a member of the TGFβ superfamily. BMP9 induced platinum resistance by activating EMT in HO8910 and SKOV3 cell lines [113]. Furthermore, tumor-derived TGFβ stimulated TGFβ secretion by mesothelial cells with subsequent phosphorylation of Smad2 and induction of Zeb1.…”

Section: Emt and Chemotherapy Resistancementioning

confidence: 99%

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

Loret

Denys

Tummers

et al. 2019

Cancers

194

134

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Ovarian cancer is the most lethal of all gynecologic malignancies and the eighth leading cause of cancer-related deaths among women worldwide. The main reasons for this poor prognosis are late diagnosis; when the disease is already in an advanced stage, and the frequent development of resistance to current chemotherapeutic regimens. Growing evidence demonstrates that apart from its role in ovarian cancer progression, epithelial-to-mesenchymal transition (EMT) can promote chemotherapy resistance. In this review, we will highlight the contribution of EMT to the distinct steps of ovarian cancer progression. In addition, we will review the different types of ovarian cancer resistance to therapy with particular attention to EMT-mediated mechanisms such as cell fate transitions, enhancement of cancer cell survival, and upregulation of genes related to drug resistance. Preclinical studies of anti-EMT therapies have yielded promising results. However, before anti-EMT therapies can be effectively implemented in clinical trials, more research is needed to elucidate the mechanisms leading to EMT-induced therapy resistance.

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Section: Emt and Chemotherapy Resistancementioning

confidence: 99%

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

Loret

Denys

Tummers

et al. 2019

Cancers

194

134

View full text Add to dashboard Cite

show abstract

“…Expression of STYK1 (serine/threonine/tyrosine kinase 1, also known as NOK, a novel oncogene with kinase-domain) is aberrant in many malignancies ( Moriai et al, 2006 ; Jackson et al, 2009 ; Kondoh et al, 2009 ; Orang et al, 2014 ; Chen et al, 2016 , 2017 ; Hu et al, 2018 ). Moreover, overexpressed STYK1 likely stimulates cancer development by sustaining proliferative signaling, leading to abnormal proliferation of cancer cells ( Chung et al, 2009 ; Cao et al, 2016 ; Chen et al, 2016 ), enhancing the resistance of tumor cells to programmed cell death ( Lai et al, 2019 ; Shi et al, 2019 ), promoting the Warburg effect, remodeling cellular energetics in malignant cells ( Shi et al, 2017 ; Zhao et al, 2017 ), and stimulating angiogenesis and lymphangiogenesis during tumor progression ( Liu et al, 2016 ). In addition, a high level of STYK1 downregulates the expression of E-cadherin ( Chen et al, 2005 , 2017 ) and induces EMT via MAPK/ERK and PI3K/AKT signaling ( Chen et al, 2016 , 2017 ; Wang et al, 2016 ), indicating that STYK1 expression correlates with EMT and metastasis, although the precise mechanisms underpinning this relationship need to be further studied.…”

Section: Introductionmentioning

confidence: 99%

STYK1/NOK Promotes Metastasis and Epithelial-Mesenchymal Transition in Non-small Cell Lung Cancer by Suppressing FoxO1 Signaling

Lai

Lin

Wang

et al. 2021

Front. Cell Dev. Biol.

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AimsSerine/threonine/tyrosine kinase 1 (STYK1) has been previously shown to have oncogenic properties, and emerging evidence suggests that STYK1 expression correlates with epithelial-mesenchymal transition (EMT). However, the mechanism of STYK1 involvement in oncogenesis remains unknown. The present study aimed to elucidate how STYK1 expression level relates to the metastasis, migration, invasion, and EMT in non-small cell lung cancer (NSCLC) and to determine the molecular mechanism of STYK1 effects.MethodsSerine/threonine/tyrosine kinase 1 (STYK1) expression level and its relationship with the prognosis of NSCLC were determined using the ONCOMINE database and clinical cases. Non-small cell lung cancer cell lines with the overexpression or knockdown of STYK1 were established to determine whether STYK1 promotes cell migration, invasion, and EMT in vitro and in vivo. In addition, a constitutively active FoxO1 mutant (FoxO1AAA) was used to examine the role of FoxO1 in the STYK1-mediated upregulation of metastasis and EMT in NSCLC.ResultsSerine/threonine/tyrosine kinase 1 (STYK1) was upregulated in NSCLC tissues and cell lines, and its overexpression correlated with poor prognosis in patients with NSCLC after surgery. Enhanced expression of STYK1 potentiated the migration, invasion, and EMT in SW900 cells, thereby promoting metastasis, whereas knockdown of STYK1 inhibited these cellular phenomena in Calu-1 cells. Furthermore, STYK1 expression was positively related to the level of phosphorylated-FoxO1, whereas the constitutively active FoxO1 mutant protected against the positive effect of STYK1 overexpression on cell migration, invasion, and EMT.ConclusionSerine/threonine/tyrosine kinase 1 (STYK1) was upregulated in NSCLC and correlated with poor clinical outcomes. In addition, STYK1 suppressed FoxO1 functions, thereby promoting metastasis and EMT in NSCLC.

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“…Smad3, as a well-known downstream signal of TGFβ1, can be activated by phosphorylated ALK5 after binding of TGFβ1 to its receptor ( 16 ). Since the TGFβ1/Smad3 signal transduction pathway is involved in inducing EMT in ovarian cancer ( 17 ), we aimed to identify whether the TGFβ1/Smad3 pathway is more activated in 3D-cultured ovarian cancer spheroids than in 2D-cultured ovarian cancer cells. As shown in Figure 1B , higher phosphorylation levels of Smad3 were found in 3D-cultured HEY and A2780 cells than in 2D-cultured cells, which indicated that TGFβ1/Smad3 might play a role in promoting the EMT process in ovarian cancer spheroids.…”

Section: Resultsmentioning

confidence: 99%

A SMYD3/ITGB6/TGFβ1 Positive Feedback Loop Promotes the Invasion and Adhesion of Ovarian Cancer Spheroids

et al. 2021

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BackgroundImplantation metastasis is the main means of dissemination in ovarian cancer. Our previous studies showed that SET and MYND domain-containing protein 3 (SMYD3) expression was higher in ovarian cancer spheroids than in monolayers. SMYD3 enhancement of spheroid invasion and adhesion is mediated by the downstream effectors ITGB6 and ITGAM. However, the potential mechanisms underlying the SMYD3/integrin-mediated invasion and adhesion of spheroids still need to be explored.MethodsWestern blotting was used to examine the expression of SMYD3, ITGB6 and downstream molecules under different treatments. Immunofluorescence was used to detect the expression of F-actin, E-cadherin and N-cadherin. Anti-ITGB6 antibody-based inhibition and dual-luciferase reporter assays were used to confirm the binding between ITGB6 and latent TGFβ1. Transwell invasion, adherence and 3D tumor spheroid invasion assays were employed to test the effects of TGFβ1 on the invasion and adhesion of ovarian cancer spheroids. ELISA was performed to assess the release of latent TGFβ1 from ovarian cancer spheroids.ResultsSMYD3 and ITGB6 activated the TGFβ1/Smad3 pathway and then induced the upregulation of Snail, Vimentin and N-cadherin and the downregulation of E-cadherin in 3D-cultured ovarian cancer spheroids. In this process, latent TGFβ1 could bind to ITGB6 and become activated to stimulate the Smad3 pathway. Moreover, SMYD3 and ITGB6 could facilitate the release of latent TGFβ1 from 3D-cultured ovarian cancer spheroids. Interestingly, TGFβ1 could promote the expression of SMYD3 and ITGB6 via feedback. This positive feedback loop could further amplify the biological effect and promote the invasion and adhesion of ovarian cancer spheroids.ConclusionOur results demonstrated that the SMYD3/ITGB6/TGFβ1-Smad3 positive feedback loop could promote the invasion and adhesion of ovarian cancer spheroids by upregulating the expression of N-cadherin, Snail, and Vimentin and downregulating the expression of E-cadherin. Thus, our study unmasked the mechanism of SMYD3- and ITGB6-induced ovarian cancer metastasis and provides new ideas for targeted ovarian cancer treatment.

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SMAD3 inducing the transcription of STYK1 to promote the EMT process and improve the tolerance of ovarian carcinoma cells to paclitaxel

Cited by 14 publications

References 54 publications

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

STYK1/NOK Promotes Metastasis and Epithelial-Mesenchymal Transition in Non-small Cell Lung Cancer by Suppressing FoxO1 Signaling

A SMYD3/ITGB6/TGFβ1 Positive Feedback Loop Promotes the Invasion and Adhesion of Ovarian Cancer Spheroids

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