Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

Zhang, Xueying; Cao, Jinglin; Pei, Yujun; Zhang, Jiyan; Wang, Qingyang

doi:10.3892/ol.2016.4427

Cited by 13 publications

(13 citation statements)

References 34 publications

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“…Although these results are consistent with EGFR activation at Y1173, which has been implicated in downstream activation of the MAPK/ERK cascade (62), additional studies are warranted to better understand how SMAD4 loss might influence site-specific phosphorylation changes of activated EGFR. Furthermore, a recent study reporting that SMAD4 may execute its tumor suppressive function via attenuation of JNK/MAPK activation (63), parallels our observation that pJNK level was significantly upregulated in SMAD4 depleted cells. Moreover, reconstitution of the SMAD4 expression in a SMAD4-negative cell line resulted in marked inhibition of cell growth and concomitant reduction in MAPK and JNK phosphorylation, suggesting that dysregulation of MAPK and JNK signaling may contribute to cetuximab resistance in subset of HPV-negative HNSCC tumors expressing low SMAD4 level.…”

Section: Discussionsupporting

confidence: 89%

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

Ozawa

Ranaweera

Izumchenko

et al. 2017

Clinical Cancer Research

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Purpose We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design SMAD4 expression was assessed by immunohistochemistry in 130 newly diagnosed and 43 recurrent HNSCC patients. Correlative statistical analysis with clinicopathological data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo. Results Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of pro-survival and anti-apoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in a HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo. We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors.

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Section: Discussionsupporting

confidence: 89%

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

Ozawa

Ranaweera

Izumchenko

et al. 2017

Clinical Cancer Research

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“…Previous studies demonstrated that miR-146a was involved in the development and metastasis in cancers ( 26 , 28 ). Here, clinicopathological analysis suggested that the increased levels of miR-146a were notably related with TNM stage and lymph node metastasis in patients with MM.…”

Section: Discussionmentioning

confidence: 99%

miR-146a promotes cell migration and invasion in melanoma by directly targeting SMAD4

Shang

Shao

et al. 2018

Oncol Lett

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Previous studies have explored the functions of microRNA (miR)-146a in different types of cancer through mediating different targets. However, the roles of miR-146a in malignant melanoma (MM) cell migration and invasion remain largely elusive. In the present study, the potential molecular function of miR-146a in MM was investigated. Reverse transcription-quantitative polymerase chain reaction was utilized to detect miR-146a expression in MM tissues and cell lines. A Transwell assay was performed to confirm the ability of migration and invasion. A luciferase assay and biological analysis were used to predict and determine the targets of miR-146a. The expression of miR-146a was upregulated in melanoma tissues and cell lines. Clinicopathological analysis indicated that the miR-146a level was negatively correlated with the progression of melanoma. Abnormal expression of miR-146a promoted cell migration and invasion in MM cells. Additionally, it was also observed that Mothers against decapentaplegic homolog 4 (SMAD4) was a novel target of miR-146a in MM. SMAD4 was negatively associated with miR-146a in MM and abnormal expression of SMAD4 attenuated miR-146a-mediated promotion of cell migration and invasion. In conclusion, miR-146a functioned as an oncogene by directly targeting SMAD4 and it may be a novel diagnostic and therapeutic marker of MM.

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“…CFPAC-1 cells harbor allelic deletion in the SMAD4 gene, inducing the inactivation of SMAD4. Loss of SMAD4 causes alterations to multiple kinase pathways, including the p38 and AKT pathways, and increases chemoresistance in vitro (28,29). The results of the present study indicated that high concentrations of EEIHL can downregulate the phosphorylation of AKT and STAT3, affecting mitochondrial apoptotic proteins, including Bim, Mcl-1 and Bcl-2.…”

Section: Discussionmentioning

confidence: 52%

Ethyl acetate extract from Inulaï¿½helenium L. inhibits the proliferation of pancreatic cancer cells by regulating the STAT3/AKT pathway

et al. 2018

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Sesquiterpene lactones are bioactive compounds that have been identified as responsible for the anticancer activity of the medicinal herb, Inula helenium L. (IHL). However, the mechanisms of action involved in the anti‑pancreatic cancer activity of IHL have yet to be elucidated. The present study used an optimized extraction strategy to obtain sesquiterpene lactones from IHL (the resulting product termed ethyl acetate extract of IHL; EEIHL), and examined the potential mechanisms involved in the anti‑pancreatic cancer activity of EEIHL. Ethanol and ethyl acetate were used to extract sesquiterpene lactones from IHL to give the final product EEIHL. Cell Counting Kit‑8, colony formation and Annexin V/propidium iodide assays were used to detect the anti‑proliferative activity of EEIHL. Cell migration was determined with a wound healing assay. mRNA and protein expression levels were analyzed by reverse transcription‑quantitative polymerase chain reaction and western blot analyses, respectively. It was identified that low concentrations of EEIHL caused CFPAC‑1 cell cycle arrest in the G0/G1 phase, whereas high concentrations of EEIHL induced mitochondria‑dependent apoptosis. In addition, EEIHL could inhibit the phosphorylation of the signal transducer and activator of transcription (STAT)3/AKT pathway, potentially resulting in impeded cell mobility. In conclusion, EEIHL could activate mitochondrial‑dependent apoptosis and inhibit cell migration through the STAT3/AKT pathway in CFPAC-1 cells.

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Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

Cited by 13 publications

References 34 publications

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

miR-146a promotes cell migration and invasion in melanoma by directly targeting SMAD4

Ethyl acetate extract from Inulaï¿½helenium L. inhibits the proliferation of pancreatic cancer cells by regulating the STAT3/AKT pathway

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