Targeting the ERK pathway reduces liver metastasis of Smad4-inactivated colorectal cancer

Ai, Xi; Wu, Yanhui; Zhang, Wei; Zhang, Zhanguo; Jin, Guan-Nan; Zhao, Jianping; Yu, Jingjing; Lin, Yandan; Zhang, Wanguang; Liang, Huifang; Datta, Pran K.; Zhang, Mingzhi; Zhang, Bixiang; Chen, Xiaoping

doi:10.4161/cbt.26427

Cited by 24 publications

(20 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…• • TGF-β/Smad pathway TGF-β/Smad signaling pathway has been found to be implicated in CRC carcinogensis [34]. Two serine-threonine kinase receptors TGF-βR I and TGF-βR II are the membrane receptors located in the upstream of the TGF-β/Smad signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Cellular Signaling Pathways Implicated in Metastasis of Colorectal Cancer and the Associated Targeted Agents

Liu

Zhang

et al. 2015

Future Oncol.

View full text Add to dashboard Cite

Colorectal cancer (CRC) is the third leading cancer worldwide and CRC-related death is mainly attributed to metastasis. Many cellular signaling pathways have been demonstrated to be aberrant in colorectal tumors, and some of them lead to the acquisition of malignant phenotypes. Therefore, the evaluation of signaling pathways implicated in CRC metastasis is urgent for further understanding of CRC progression and pharmacotherapy. This review focuses on several novel cellular signaling pathways associated with CRC metastasis, including Wnt/β-catenin, p53, COX, TGF-β/Smad, NF-κB, Notch, VEGF and JAKs/STAT3 signaling pathways. Targeted agents developed based on these pathways are also briefly discussed.

show abstract

Section: Introductionmentioning

confidence: 99%

Cellular Signaling Pathways Implicated in Metastasis of Colorectal Cancer and the Associated Targeted Agents

Liu

Zhang

et al. 2015

Future Oncol.

View full text Add to dashboard Cite

show abstract

“…12,13 Overall, PDA studies support the notion that disabling TGF-β/Smad4 signaling pathway may be a critical event in pancreatic cancer progression, and open up a specific route toward the design of biomarkers as well as adjuvant therapies for this pathology. 14 To date, although studies involving stromal components are revealing some potential therapeutic targets, genetic and epigenetic studies have identified mutated/altered pathways in the tumor cells engulfed within the tumor mass, consisting mainly of KRAS, CDKN2A, SMAD4/DPC4, Hedgehog and TP53 mutations, among others. 15,16 Interestingly, considering their involvement in events linked with control of cellular proliferation, the role of the first four pathways is fairly well described, however, the impact of p53 mutations remains unclear.…”

mentioning

confidence: 99%

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

View full text Add to dashboard Cite

Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/ activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.

show abstract

“…Sun et al reported that RBPMS acts as a coactivator of transcriptional activity through Smad2, Smad3 and Smad4 to promote the nuclear accumulation of Smad4 protein. Also, it is confirmed that Smad4 is negatively related with the phosphorylation of ERK in human metastatic CRC cells . In order to investigate the potential mechanism of miR‐21‐3p in regulating the progress of CRC, the phosphorylation level of ERK and the nuclear level of Smad4 in HCT116 cells transfected with miR‐21‐3p inhibitors or NC‐miRNA were tested by western blot analysis (Figure A).…”

Section: Resultsmentioning

confidence: 93%

Inhibition of microRNA‐21‐3p suppresses proliferation as well as invasion and induces apoptosis by targeting RNA‐binding protein with multiple splicing through Smad4/extra cellular signal‐regulated protein kinase signalling pathway in human colorectal cancer HCT116 cells

Hou

Guo

Zhao

et al. 2018

Clin Exp Pharma Physio

View full text Add to dashboard Cite

MicroRNA-21-3p (miR-21-3p), the passenger strand of pre-mir-21, has been found to be high-expressing in various cancers and to be associated with tumour malignancy, which is proposed as a novel focus in malignant tumours. Colorectal cancer (CRC), currently known as one of the most prevalent malignancy, is a leading cause of cancer death. This study aimed to investigate the key role of miR-21-3p in CRC by inhibiting its expression using transfection with miR-21-3p inhibitors into human CRC HCT116 cells. Results showed that the expression of miR-21-3p was higher than other CRC cells used in the study including Lovo, HT29, Colo320 and SW480 cells, inhibition of which suppressed the proliferation and induced cell cycle arrest in HCT116 cells. Besides, transfection with miR-21-3p inhibitors also attenuated cell migration and invasion, and induced apoptosis as well. Moreover, luciferase assay confirmed RBPMS as a direct target of miR-21-3p in HCT116 cells. Further, miR-21-3p inhibitors increased the nuclear accumulation of Smad4 and reduced phosphorylation of ERK. Interestingly, we found that silence of RBPMS using RNA interference (siRNA) not only elevated the cell viability but also increased the phosphorylation of ERK and reversed the nuclear accumulation of Smad4 induced by miR-21-3p inhibitors in HCT116 cells. Data suggest that inhibition of miR-21-3p suppresses cell proliferation, invasion as well as migration and induces apoptosis by directly targeting RBPMS through Smad4/ERK signalling pathway in HCT116 cells. Our study demonstrates miR-21-3p as a potent target for suppressing tumour progression of CRC which may have implications in CRC therapy in the future.

show abstract

Targeting the ERK pathway reduces liver metastasis of Smad4-inactivated colorectal cancer

Cited by 24 publications

References 37 publications

Cellular Signaling Pathways Implicated in Metastasis of Colorectal Cancer and the Associated Targeted Agents

Cellular Signaling Pathways Implicated in Metastasis of Colorectal Cancer and the Associated Targeted Agents

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

Inhibition of microRNA‐21‐3p suppresses proliferation as well as invasion and induces apoptosis by targeting RNA‐binding protein with multiple splicing through Smad4/extra cellular signal‐regulated protein kinase signalling pathway in human colorectal cancer HCT116 cells

Contact Info

Product

Resources

About