Loss of WISP2/CCN5 in Estrogen-Dependent MCF7 Human Breast Cancer Cells Promotes a Stem-Like Cell Phenotype

Ferrand, Nathalie; Gnanapragasam, Anne; Dorothée, Guillaume; Redeuilh, Gérard; Larsen, Annette K.; Sabbah, Michèle

doi:10.1371/journal.pone.0087878

Cited by 36 publications

(40 citation statements)

References 58 publications

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“…In this case, the protection from CTL‐mediated lysis appeared to be linked with the activation of an autophagic program, which may contribute to promote survival in these cells. A similar impairment of CTL‐mediated lysis was also noted in another model of MCF7 cells undergoing EMT (Akalay et al ., ) wherein silencing of WISP2 (WNT1‐inducible signaling pathway protein 2) coincides with hyperactivity of TGF‐β signaling, EMT, and acquisition of stemness properties (Ferrand et al ., ; Fritah et al ., ). In this instance, the autophagy status did not appear to be involved in the resistant phenotype; however, a disruption of TGF‐β signaling in these cells by treatment with A83‐01, an inhibitor of TGF‐β‐related type I receptors ALK5, ALK4, and ALK7, effectively decreased resistance to CTLs.…”

Section: The Acquisition Of a Mesenchymal Phenotype Is Associated Witmentioning

confidence: 97%

New insights into the role of EMT in tumor immune escape

et al. 2017

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Novel immunotherapy approaches have provided durable remission in a significant number of cancer patients with cancers previously considered rapidly lethal. Nonetheless, the high degree of nonresponders, and in some cases the emergence of resistance in patients who do initially respond, represents a significant challenge in the field of cancer immunotherapy. These issues prompt much more extensive studies to better understand how cancer cells escape immune surveillance and resist immune attacks. Here, we review the current knowledge of how cellular heterogeneity and plasticity could be involved in shaping the tumor microenvironment (TME) and in controlling antitumor immunity. Indeed, recent findings have led to increased interest in the mechanisms by which cancer cells undergoing epithelial‐mesenchymal transition (EMT), or oscillating within the EMT spectrum, might contribute to immune escape through multiple routes. This includes shaping of the TME and decreased susceptibility to immune effector cells. Although much remains to be learned on the mechanisms at play, cancer cell clones with mesenchymal features emerging from the TME seem to be primed to face immune attacks by specialized killer cells of the immune system, the natural killer cells, and the cytotoxic T lymphocytes. Recent studies investigating patient tumors have suggested EMT as a candidate predictive marker to be explored for immunotherapy outcome. Promising data also exist on the potential utility of targeting these cancer cell populations to at least partly overcome such resistance. Research is now underway which may lead to considerable progress in optimization of treatments.

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Section: The Acquisition Of a Mesenchymal Phenotype Is Associated Witmentioning

confidence: 97%

New insights into the role of EMT in tumor immune escape

et al. 2017

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“…11,19 To examine directly whether the TGF-b signaling pathway modulated PD-L1 expression, MCF7 sh-WISP2 and MDA-MB-231 cells were treated with two different inhibitors of TGFb signaling. However, as illustrated in Fig.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200

et al. 2017

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PD-L1 expression and regulation by mesenchymal tumor cells remain largely undefined. Here, we report that among different EMT-activated MCF7 human breast cancer cell clones, PD-L1 was differentially upregulated in MCF7 sh-WISP2, MCF7-1001/2101, and MDA-MB-231 cells but not in MCF7 SNAI1 and MCF7 SNAI1-6SA cells. Mechanistic investigations revealed that siRNA silencing of ZEB-1, but not SNAI1, TWIST, or SLUG and overexpression of miR200 family members in MCF7 sh-WISP2 cells strongly decreased PD-L1 expression. Thus, we propose that PD-L1 expression in EMT-activated breast cancer cells depends on the EMT-TF involved in EMT activation. Interestingly, siRNA-mediated targeting of PD-L1 or antibodymediated PD-L1 block restored the susceptibility of highly resistant MCF7 sh-WISP2 and MCF7-2101 cells to CTL-mediated killing. Additionally, these results provide a novel preclinical rationale to explore EMT inhibitors as adjuvants to boost immunotherapeutic responses in subgroups of patients in whom malignant progression is driven by different EMT-TFs. KEYWORDSBreast cancer; epithelial-tomesenchymal transition; miR-200 and immunotherapy; PD-L1; SLUG (SNAI2); SNAI1; ZEB-1

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“…We highlighted that WISP2/CCN5 may be a promising therapeutic target and development of WISP2/CCN5 promoter would have a great impact on breast cancer therapy. The relationship between deficiency of WISP2/CCN5 and estrogen dependent MCF-7 has been explored because WISP2/CCN5 is an estrogen response gene in ER-α-positive breast cancer cells, such as MCF-7 cell line, and present studies showed that the estradiol-treatment is able to activate CCN5 transcription [31][32][33] . Therefore, correlation between WISP2/CCN5 and ER, PR and Her-2 still need to be detected in breast cancer.…”

Section: Secondmentioning

confidence: 80%

WISP2/CCN5gene knockdown in vitro and in vivo exhibits proliferation promotion of breast cancer through targeting Skp2 and p27Kip1

Zhang

et al. 2020

Preprint

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BackgroundEmerging evidence has demonstrated that WISP2/CCN5 is critically involved in tumorigenesis. However, the function of WISP2/CCN5 in breast cancer carcinogenesis is largely unclear. Methodswe aim to explore the effects and potential mechanisms of WISP2/CCN5 on proliferation of breast cancer cells and carcinogenesis of breast cancer xenograft. Lentivirus vector with WISP2/CCN5shRNA was transfected into MCF-7, and breast cancer cells and xenograft were conducted. Effect of WISP2/CCN5 on growth and carcinogenesis of breast cancer cells and xenografts was evaluated by MTT assay and tumor volume. The relationship between WISP2/CCN5, Skp2 and p27Kip1 was detected in vitro and in vivo by RT-PCR at mRNA level and Western blotting at protein level． Results The result of MTT assay indicated that MCF-7 cell growth viability in WISP2/CCN5 gene knockdown group was significantly higher than negative vector group(P＜0.05) or control group (P＜0.05). It suggested that knockdown of WISP2/CCN5 gene by shRNA lentivirus plasmid promoted proliferation of MCF-7 cells. The growth curves of breast cancer xenograft showed that xenografts in WISP2/CCN5 knockdown group grew more quickly than negative vector group(P＜ 0.05) or control group (P＜ 0.05). Subsequently, the results of RT-PCR and Western blotting revealed that WISP2/CCN5 gene knockdown led to increased Skp2 and decreased p27Kip1 at mRNA and protein levels. WISP2/CCN5 exerts its inhibition on proliferation of MCF-7 cell line and suppressive functions on growth of breast carcinoma via regulation of Skp2 and p27Kip1at mRNA and protein levels. However, WISP2/CCN5 gene knockdown resulted in loss of inhibition effect on MCF-7 and breast cancer. ConclusionsOur findings suggest that WISP2/CCN5 could be a useful therapeutic strategy for the treatment of breast cancer through targeting Skp2 and p27Kip1.

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Loss of WISP2/CCN5 in Estrogen-Dependent MCF7 Human Breast Cancer Cells Promotes a Stem-Like Cell Phenotype

Cited by 36 publications

References 58 publications

New insights into the role of EMT in tumor immune escape

New insights into the role of EMT in tumor immune escape

The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200

WISP2/CCN5gene knockdown in vitro and in vivo exhibits proliferation promotion of breast cancer through targeting Skp2 and p27Kip1

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