Hypoxia‐inducible transgelin 2 selects epithelial‐to‐mesenchymal transition and γ‐radiation‐resistant subtypes by focal adhesion kinase‐associated insulin‐like growth factor 1 receptor activation in non‐small‐cell lung cancer cells

Kim, In-Gyu; Lee, Jei-Ha; Kim, Seo-Yeon; Hwang, Hai-Min; Kim, Taerim; Cho, Eun‐Wie

doi:10.1111/cas.13791

Cited by 27 publications

(23 citation statements)

References 63 publications

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“…26 During tumor progression, TGF-β signaling was also found to be involved in the EMT that is critical in colorectal cancer, in which TGF-β activates RhoA and rho-associated protein kinase to induce actin polymerization. 15,21,27 In our study, we found TGF-βdependent activation of TAGLN expression is accompanied with decreased expression of E-cadherin, and increased levels of vimentin, fibronectin. It has been shown that TGF-β induced activation of TAGLN expression in tumor cells, especially in epithelial cells, can lead to a process of EMT, and TGF-β stimulated fibroblasts can lead to their transformation into myofibroblasts, which is important in tumor progression.…”

Section: Discussionsupporting

confidence: 54%

TAGLN and High-mobility Group AT-Hook 2 (HMGA2) Complex Regulates TGF-β-induced Colorectal Cancer Metastasis

Zhou¹,

Li²,

Xie³

et al. 2020

OTT

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Background: Colorectal cancer is one of the three most common cancers worldwide. Altered TGF-β signaling pathway in colorectal cancer is associated with metastasis and poor prognosis. It is also involved in epithelial-to-mesenchymal transition (EMT), which is essential in progression and metastasis. This study aims to investigate the role of transgelin (TAGLN) and high-mobility group AT-hook 2 (HMGA2) in the progression of colon cancer. Methods: HT29 and HCT116 cells were treated with TGF-β, and the effects of inhibition of TAGLN and overexpression of HMGA2 on TGF-β treated cell on cell migration and invasion, expression of EMT markers, including E-cadherin, vimentin and fibronectin were detected as well as MMP2 and MMP9, which are critical in cancer cell metastasis. The interaction of TAGLN and HMGA2 was also investigated by using co-immunoprecipitation. The function of TAGLN in tumor metastasis and growth was investigated in vivo. Results: We found that TGF-β could significantly promote the migration of HT29 and HCT116 cells, as well as TAGLN protein expression and nucleus translocation, while inhibition of TAGLN could effectively reverse the effects of TGF-β on HT29 and HCT116 cells, which was observed in terms of decreased cell migration and invasion. Knockdown of TAGLN could also rescue TGF-β-induced loss of E-cadherin, and decreased TGF-β-induced vimentin and fibronectin expression; the elevation of MMP9 and MMP2 was also reversed by inhibition of TAGLN. Further investigation confirmed the interaction of HMGA2 and TAGLN, as overexpression of HMGA2 restores the effects of TGF-β on HT29 cells, which were attenuated by TAGLN inhibition both in vitro and in vivo. Conclusion: Overall, our study revealed that interaction between TAGLN and HMGA2 was involved in TGF-β-induced cell migration and promotion of colon cancer cells, suggesting that HMGA2 and TAGLN are potential molecular targets to prevent colon cancer progression.

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Section: Discussionsupporting

confidence: 54%

TAGLN and High-mobility Group AT-Hook 2 (HMGA2) Complex Regulates TGF-β-induced Colorectal Cancer Metastasis

Zhou¹,

Li²,

Xie³

et al. 2020

OTT

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“…It is associated with stem cells, and acquisition of stem-like properties and quiescence [ 23 ]. In hypoxic cancer cells, Transgelin 2 (TAGLN2), an actin-binding protein, is induced, while in parallel, Snail1 is increased, leading to the induction of the EMT by downregulating the expression of E-cadherin [ 22 , 24 ]. The solute carrier family 1 (glial high affinity glutamate transporter), member 3 (SLC1A3), a glutamate transporter, mediates inter-niche stem cell activation [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

jouvence, a new human snoRNA involved in the control of cell proliferation

2020

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Background Small nucleolar RNAs (snoRNAs) are non-coding RNAs that are conserved from archaebacteria to mammals. They are associated in the nucleolus, with proteins to form small nucleolar ribonucleoprotein (snoRNPs). They modify ribosomal RNAs, for example, the H/ACA box that converts uridine to pseudouridine. In humans, various pathologies have been associated with snoRNAs, and several snoRNAs have been reported to participate in many cancer processes. Recently, a new H/ACA box snoRNA named jouvence has been identified in Drosophila and has been shown to be involved in lifespan determination in relation to gut homeostasis. Because snoRNAs are conserved through evolution, both structurally and functionally, a jouvence orthologue has been identified in humans. RT-PCR has revealed that jouvence is expressed, suggesting that it might be functional. These results suggest the hypothesis that jouvence may display similar functions, including increasing the healthy lifespan in humans. Results Here, we report the characterization of the human snoRNA jouvence, which has not yet been annotated in the genome. We show that its overexpression significantly stimulates cell proliferation, both in various stable cancerous cell lines as well as in primary cells. By contrast, its knockdown by siRNA leads to the opposite phenotype, a rapid decrease in cell proliferation. Transcriptomic analysis (RNA-Seq) revealed that the overexpression of jouvence leads to a dedifferentiation signature of the cells. Conversely, the knockdown of jouvence led to a striking decrease in the expression levels of genes involved in ribosome biogenesis and the spliceosome. Conclusion The overexpression of a single and short non-coding RNA of 159 nucleotides, the snoRNA-jouvence, seems to be sufficient to reorient cells toward stemness, while its depletion blocks cell proliferation. In this context, we speculate that the overexpression of jouvence, which appears to be a non-canonical H/ACA snoRNA, could represent a new tool to fight against the deleterious effects of aging, while inversely, its knockdown by siRNA could represent a new approach in cancer therapy.

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“…Furthermore, a study on the tumor microenvironment of NSCLC demonstrated that the activation of the IGF1Rβ/PI3K/ AKT pathway by hypoxia could induce EMT, which might subsequently enhance radioresistance. 51 Consequently, we inferred that in NSCLC cells, radioresistance with enhanced DNA damage repair might be promoted by the miR-410-induced EMT process. However, to clearly understand the correlation between miR-410-induced EMT and radioresistance, a separate and effective tracing system is needed to monitor the EMT process because the EMT phenotype is reversible and transient.…”

Section: Discussionmentioning

confidence: 96%

miR-410 induces both epithelial–mesenchymal transition and radioresistance through activation of the PI3K/mTOR pathway in non-small cell lung cancer

Yue

Liao

et al. 2020

Sig Transduct Target Ther

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Radiotherapy remains one of the major treatments for non-small cell lung cancer (NSCLC) patients; whereas intrinsic or acquired radioresistance limits its efficacy. Nevertheless, most studies so far have only focused on acquired resistance. The exact mechanisms of intrinsic radioresistance in NSCLC are still unclear. A few studies have suggested that epithelial-mesenchymal transition (EMT) is associated with radioresistance in NSCLC. However, little is known about whether the abnormal expression of specific microRNAs induces both EMT and radioresistance. We previously found that miR-410 has multiple roles as an oncomiRNA in NSCLC. In this study, we revealed that miR-410 overexpression promoted EMT and radioresistance, accompanied by enhanced DNA damage repair both in vitro and in vivo. Conversely, knockdown of miR-410 showed the opposite effects. We further demonstrated that PTEN was a direct target of miR-410 by using bioinformatic tools and dual-luciferase reporter assays, and the miR-410-induced EMT and radioresistance were reversed by PI3K, Akt, and mTOR inhibitors or by restoring the expression of PTEN in NSCLC cells. In addition, we preliminarily found that the expression of miR-410 was positively correlated with EMT and negatively associated with the expression of PTEN in NSCLC specimens. In summary, these results demonstrated that miR-410 is an important regulator on enhancing both NSCLC EMT and radioresistance by targeting the PTEN/PI3K/mTOR axis. The findings suggest that miR-410-induced EMT might significantly contribute to the enhanced radioresistance. Therefore, miR-410 may serve as a potential biomarker or therapeutic target for NSCLC radiotherapy.

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Hypoxia‐inducible transgelin 2 selects epithelial‐to‐mesenchymal transition and γ‐radiation‐resistant subtypes by focal adhesion kinase‐associated insulin‐like growth factor 1 receptor activation in non‐small‐cell lung cancer cells

Cited by 27 publications

References 63 publications

<p><em>TAGLN</em> and High-mobility Group AT-Hook 2 (HMGA2) Complex Regulates TGF-β-induced Colorectal Cancer Metastasis</p>

<p><em>TAGLN</em> and High-mobility Group AT-Hook 2 (HMGA2) Complex Regulates TGF-β-induced Colorectal Cancer Metastasis</p>

jouvence, a new human snoRNA involved in the control of cell proliferation

miR-410 induces both epithelial–mesenchymal transition and radioresistance through activation of the PI3K/mTOR pathway in non-small cell lung cancer

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