miR-29b Mediates NF-κB Signaling in KRAS-Induced Non–Small Cell Lung Cancers

Langsch, Stephanie; Baumgartner, Ulrich; Haemmig, Stefan; Schlup, Cornelia; Schäfer, Stephan; Berezowska, Sabina; Rieger, Gregor; Dorn, Patrick; Tschan, Mario P.; Vassella, Erik

doi:10.1158/0008-5472.can-15-2580

Cited by 56 publications

(55 citation statements)

References 46 publications

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“…This miR family has been well recognized as an important regulator of collagen expression and heart fibrosis [25,26]. More recent studies revealed that miR-29a and miR-29b regulate apoptosis by targeting different genes [27,28]. Altered expression of miR-29b has been detected in multiple tumors and leukemia [28,29], raising the intriguing possibility that aberrant miR-29b expression and/or function may be associated with dysfunction of the apoptosisrelated pathway.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Jing

Yang²,

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. Methods: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. Results: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3′ untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. Conclusions: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Jing

Yang²,

Jiang

et al. 2018

Cell Physiol Biochem

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“…For example, the overexpression of miR-10b in adenomyotic epithelial cells suppresses the cell migration and invasion [13]. MiRNA-29b (miR-29b) is an important member of the miRNA family [14] and has been demonstrated to be dysregulated in many tumors [15-17]. Particularly, it has been demonstrated that miR-29b can serve as a tumor suppressor that inhibits the proliferation process of cancer cells [18].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-29b Inhibits Angiogenesis by Targeting VEGFA through the MAPK/ERK and PI3K/Akt Signaling Pathways in Endometrial Carcinoma

Chen

Tan

et al. 2017

Cell Physiol Biochem

103

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Objective: The purpose of this study is to explore the effects of microRNA-29b (miR-29b) regulating MAPK/ERK and PI3K/Akt signaling pathways on angiogenesis in endometrial carcinoma (EC) by targeting VEGFA. Methods: Between February 2013 and April 2015, 126 EC patients admitted to the Second Affiliated Hospital of Nanchang University were randomly selected, with 126 EC tissues and the corresponding adjacent normal tissues collected after surgery. The human EC cell lines RL-95-2 and HEC-1-B and human endometrial cells were assigned to the normal group (human endometrial cells), the blank group (untransfected RL-95-2 or HEC-1-B cells), the pMIR-control group (RL-95-2 or HEC-1-B cells transfected with an empty vector), the pMIR-miR-29b group (RL-95-2 or HEC-1-B cells transfected with the miR-29b plasmid), LNA-control group (RL-95-2 or HEC-1-B cells transfected with an oligonucleotide inhibitors control), the LNA-miR-29b inhibitors group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNA^{^TM} miR-29b inhibitors), the LNA-miR-29b inhibitors + PD98059 group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNA^{^TM} miR-29b inhibitors and PD98059, an inhibitor of the MAPK/ERK signaling pathway) and the LNA-miR-29b inhibitors + wortmannin group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNA^{^TM} miR-29b inhibitors and wortmannin, an inhibitor of the PI3K/Akt signaling pathway). qRT-PCR and Western blotting were conducted to detect the miR-29b expression and the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2. Immunohistochemistry (IHC) was performed to determine the microvessel density (MVD) expression in the EC tissues, adjacent normal tissues and nude-mice. Results: Compared with the adjacent normal tissues, miR-29b expression was down-regulated, the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were up-regulated, and MVD expression was increased in the EC tissues. Compared with the normal group, miR-29b expression was down-regulated, while the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were up-regulated in the other groups. Compared with the blank, pMIR-control and LNA-control groups, miR-29b expression was increased, while mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were decreased in the pMIR-miR-29b group. The LNA-miR-29b inhibitors group exhibited elevated miR-29b expression and decreased mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 (All P < 0.05). Additionally, miR-29b expression was reduced in the LNA-miR-29b inhibitors + PD98059 and LNA-miR-29b inhibitors + wortmannin groups. In comparison to the normal group, MVD expression was elevated in the other groups. Compared with the blank, pMIR-control, LNA-control, LNA-miR-29b inhibitors + PD98059 and LNA-miR-29b inhibitors + wortmannin groups, MVD expression was decreased in the pMIR-miR-29b group but increased in the LNA-miR-29b inhibitors group. Conclusion: Our results indicate that miR-29b negatively mo...

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“…This different response to chemotherapy could be partially explained by different activations of downstream signaling according to the amino-acid substitution, and subsequent miRNAs up-regulation. Indeed, Langsch and co-workers have shown an increased expression of miR-29b in KRAS G12V NSLC cell lines only, leading to increase sensitivity to cisplatin (10). One can thereby speculate that in case of other amino-acid substitutions, other miRNAs are upregulated leading to different chemo-sensitivity.…”

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confidence: 99%

“…therapeutic targets (10). Indeed, NSCLC, just like many other cancers, rely in part on the balance between apoptotic and anti-apoptotic signals, with more particularly the over-expression of BCL2 and other members of its antiapoptotic family.…”

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confidence: 99%

“…Nevertheless, the work of Langsch and co-workers raises once again the notion of heterogeneity of KRAS mutations (10). Indeed, even though the worse prognostic value related to KRAS mutations in NSCLC seems to be clear (7,8), an increasing number of publications support the idea that KRAS mutations consist of a very heterogeneous group of "sub-mutations" according to the amino-acid substitutions, both molecularly and clinically.…”

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MicroRNAs: a new tool in the complex biology of KRAS mutated non-small cell lung cancer?

Renaud¹,

Seitlinger

Massard

2017

J. Thorac. Dis.

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Despite several advances in the last decades in both medical and surgical management, with a 5-year overall survival (OS) not exceeding 15%, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide (1). The past few years have seen an increased understanding in the molecular alterations of several cancers, helping clinicians to guide medical treatment and offer more accurate prognosis to patients. NSCLC was not left behind (2). Indeed, the recent discovery of oncogenic drivers such as activating mutations in the tyrosine kinase domain of the Epidermal Growth Factor Receptor (EGFR) has led to a dramatic increase in survival of patients harboring these mutations (3). Meanwhile, the prognostic and predictive values of EGFR mutations seem to be largely established in metastatic NSCLC (4), only a fleeting glimpse of clinical implications of many other mutations has been offered so far by the published literature, and might need further researches. One of the most promising molecular markers seems to rely in the mutations of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene. KRAS encodes for RAS proteins which are small GTPases bounding between inactive guanosine diphosphate (GDP) and active guanosine triphosphate (GTP) forms. RAS proteins are central mediators downstream of growth factor receptor signaling and therefore are critical for cell proliferation, survival, and differentiation. Approximately 15% to 25% of NSCLC adenocarcinomas exhibit KRAS mutations (5). In the very large majority of the cases, these mutations are missense mutations introducing an aminoacid substitution at codon 12, 13 or 61 of the exon 2 of the gene (6). This confers a constitutive activation of KRAS signaling pathways, including the PI3K-AKT-mTOR pathway, involved in cell survival, and the RAS-RAF-MEK-ERK pathway, involved in cell proliferation. The complexity of KRAS mutations is reflected by the difficulty to develop effective therapies for patients with NSCLC harboring such mutations, and so far KRAS mutations are related to a poor prognosis in both locally and advanced NSCLC patients (7,8).A promising area of research seems to be focused on microRNAs (miRNAs). miRNAs are small noncoding RNAs which act as post-translational regulator of genes. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer. They are well-known key player in downstream oncogenic pathways, behaving as oncogenes or oncosuppressors in different types of cancer. Their central role in tumorogenesis and their stable and long-lasting presence in tissues and body fluids underlie the increased efforts and interest in defining their role as possible next-generation biomarkers and targets for novel therapeutic approaches (9).The recently published paper of Langsch and co-workers offers a promising insight of the place of miRNAs in the molecular biology of KRAS-driven non-small cell lung cancer, and the possibility to use them as molecular Editorial MicroRNAs: a new tool in the co...

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miR-29b Mediates NF-κB Signaling in KRAS-Induced Non–Small Cell Lung Cancers

Cited by 56 publications

References 46 publications

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

MicroRNA-29b Inhibits Angiogenesis by Targeting VEGFA through the MAPK/ERK and PI3K/Akt Signaling Pathways in Endometrial Carcinoma

MicroRNAs: a new tool in the complex biology of KRAS mutated non-small cell lung cancer?

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