BMP4 promotes oxaliplatin resistance by an induction of epithelial-mesenchymal transition via MEK1/ERK/ELK1 signaling in hepatocellular carcinoma

Ma, Junli; Zeng, Shan; Zhang, Yan; Deng, Geng; Qu, Yanling; Guo, Cao; Yin, Ling; Han, Ying; Cai, Changjing; Li, Yiyi; Wang, Guqi; Bonkovsky, Herbert L.; Shen, Hong

doi:10.1016/j.canlet.2017.09.041

Cited by 61 publications

(53 citation statements)

References 46 publications

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“…Moreover, chemotherapy is often used before or after the abovementioned therapies. Patients suffering from advanced-stage HCC often exhibit poor prognoses or dismal clinical outcomes due to ineffective chemotherapy or a multidrug resistance (MDR) process [ 2 ]. Thus, developing a new system to test chemotherapeutic sensitivity in the treatment of HCC is necessary.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: MicroRNA-31-5p regulates chemosensitivity by preventing the nuclear location of PARP1 in hepatocellular carcinoma

Que

Zhou

You

et al. 2018

J Exp Clin Cancer Res

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BackgroundMicroRNAs (miRNAs) posttranscriptionally regulate gene expression and thereby contribute to the modulation of numerous complex and disease-relevant cellular processes, including cell proliferation, cell motility, apoptosis and stress response. miRNA-31-5p is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many hepatocellular carcinoma (HCC) tumors. Based on previous findings, we hypothesized that miR-31-5p alters chemosensitivity and that miR-31-5p mimics may influence sensitivity to chemotherapeutics in HCC as well as in a variety of other cancers.MethodsMiR-31-5p and PARP1 in HCC tissues were tested by RT-PCR and histological analysis, respectively. Next, clonogenic assay and western blot were used to detect miR-31-5p and PARP1 to modulate sensitivity to OXA-based chemotherapy. The distribution of OXA in the nuclear and intracellular was detected by ICP-MS. Coimmunoprecipitation was used to characterize the protein-protein interaction between PARP1 and ABCB9. A xenograft nude mouse model was used to examine the in vivo effects of miR-31-5p.ResultsReintroduction of miR-31-5p into miR-31-5p-null Hep3B cells significantly enhanced clonogenic resistance to oxaliplatin. Although miR-31-5p re-expression increased chemoresistance, it paradoxically increased the relative intracellular accumulation of oxaliplatin. This effect was coupled with a significantly decreased intranuclear concentration of oxaliplatin by ICP-MS. miR-31-5p prevents the nuclear location of PARP1 detected by immunofluorescence, histological analysis and Western blotting analysis. We subsequently identified an indirect miR-31-5p-mediated upregulation of ABCB9, which is a transporter associated with drug accumulation in lysosomes, along with an increased uptake of oxaliplatin to lysosomes; these phenomena were associated with a downregulation of PARP1, a bipotential transcriptional regulator with multiple miR-31-5p binding sites. However, the indirect overexpression of ABCB9 promoted cellular chemosensitivity, suggesting that miR-31-5p promotes chemoresistance largely via an ABCB9-independent mechanism.ConclusionsOverall, our data suggest that the loss of miR-31-5p from HCC tumors promotes chemosensitivity, and this knowledge may be prognostically beneficial in the context of therapeutic sensitivity.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0930-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: MicroRNA-31-5p regulates chemosensitivity by preventing the nuclear location of PARP1 in hepatocellular carcinoma

Que

Zhou

You

et al. 2018

J Exp Clin Cancer Res

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“…Resistance to treatment and relapse are often associated with the persistence of cancer SCs within their microenvironment. Indeed, BMP4 involvement in resistance to treatment has been demonstrated in several tumor types, including HCC 50 and ovarian cancer 51 . BMP type 1 receptors have also been associated with resistance in CML 38 and AML 18 , as has ΔNp73 52 .…”

Section: Discussionmentioning

confidence: 99%

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

Voeltzel¹,

Flores-Violante²,

Zylbersztejn³

et al. 2018

Cell Death Dis

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In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chronic myeloid leukemia that the bone morphogenetic proteins (BMP) pathway is involved in stem cell fate and contributes to transformation, expansion, and persistence of leukemic stem cells. Here, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in AML patients at diagnosis. BMP2 and BMP4 protein concentrations are elevated within patients’ bone marrow with a BMP4-dominant availability. This overproduction likely depends on the bone marrow microenvironment, since MNCs do not overexpress BMP4 transcripts. Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients’ outcome.

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“…9 In recent years, EMT has been implicated as an indispensable mediator of drug resistance. [10][11][12] Exploring the relationship between EMT and OXA resistance can be a promising approach for the development of therapeutic regimens to treat OXA-resistant patients.…”

Section: Introductionmentioning

confidence: 99%

<p>FOXC2 Promotes Oxaliplatin Resistance by Inducing Epithelial-Mesenchymal Transition via MAPK/ERK Signaling in Colorectal Cancer</p>

Chen¹,

Deng²,

Fu³

et al. 2020

OTT

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Background: Chemoresistance is a major obstacle to improving the survival rate of colorectal cancer (CRC) patients. Forkhead box protein C2 (FOXC2), a member of the forkhead box (Fox) transcription factor family, is reported to be an important regulator of epithelial-tomesenchymal transition (EMT) and plays a key role in tumor progression. However, little is known about the effects of FOXC2 on oxaliplatin (OXA) resistance in CRC. Methods: OXA-resistant cells were generated from HCT116 cells. CCK-8, colony formation, flow cytometry and Transwell assays were used to compare the characteristics of OXAresistant HCT116/OXA cells and the corresponding parental HCT116 cells. The expression of FOXC2 was confirmed by qRT-PCR and Western blotting in HCT116/OXA and HCT116 cells. Gain-and loss-of-function assays were performed to evaluate the effects of FOXC2 on OXA sensitivity and EMT in HCT116/OXA and HCT116 cells both in vitro and in vivo, and the possible molecular mechanisms were investigated. Results: The relative expression of FOXC2 was significantly increased in HCT116/OXA cells compared with the parental HCT116 cells. Upregulation of FOXC2 in HCT116 cells reduced OXA sensitivity and promoted EMT. However, knockdown of FOXC2 in HCT116/OXA cells markedly increased the in vitro and in vivo sensitivity of HCT116/OXA cells to OXA by regulating EMT progression. Furthermore, FOXC2 activated MAPK/ERK signaling, and blockade of ERK attenuated FOXC2-induced EMT and FOXC2-enhanced OXA resistance. Conclusion: FOXC2 induced EMT to promote oxaliplatin resistance by activating the MAPK/ERK signaling pathway. FOXC2 may be a potential therapeutic target for overcoming OXA resistance in human CRC.

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BMP4 promotes oxaliplatin resistance by an induction of epithelial-mesenchymal transition via MEK1/ERK/ELK1 signaling in hepatocellular carcinoma

Cited by 61 publications

References 46 publications

RETRACTED ARTICLE: MicroRNA-31-5p regulates chemosensitivity by preventing the nuclear location of PARP1 in hepatocellular carcinoma

RETRACTED ARTICLE: MicroRNA-31-5p regulates chemosensitivity by preventing the nuclear location of PARP1 in hepatocellular carcinoma

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

<p>FOXC2 Promotes Oxaliplatin Resistance by Inducing Epithelial-Mesenchymal Transition via MAPK/ERK Signaling in Colorectal Cancer</p>

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