CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

Martincuks, Antons; Li, Pei Chuan; Zhao, Qianqian; Zhang, Chunyan; Li, Yijia; Yu, Hua; Rodrı́guez-Rodrı́guez, Lorna

doi:10.3389/fonc.2020.589601

Cited by 50 publications

(43 citation statements)

References 255 publications

(264 reference statements)

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“…It is estimated that 70–80% of patients develop chemoresistance following initial surgery and standardized chemotherapy, although through standardized treatment, patients with OC exhibit favorable perioperative efficacy and prognosis. The development of OC chemoresistance is a complex process involving multiple factors, genes and stages, such as BRAF inhibitors and CD44 ( 28 , 29 ), and severely limits the quality of life and prognosis of patients with OC ( 6 , 30 ). The results of the present study revealed that USP46 expression levels were downregulated in OC chemoresistant tissues compared with chemosensitive tissues, suggesting that abnormal expression of USP46 may be crucial for the development of resistance in OC.…”

Section: Discussionmentioning

confidence: 99%

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Xu¹,

Zhang²,

Li³

2021

Mol Med Rep

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Ovarian cancer (OC) is a major contributor to cancer-related mortality in women. Despite numerous drugs being available for the treatment and improving the prognosis of OC, resistance to clinical chemotherapy remains a major obstacle for the treatment of advanced OC. Therefore, determining how to reverse the chemoresistance of OC has become a research hotspot in recent years. The present study aimed to reveal the potential mechanism of OC chemoresistance. Reverse transcription-quantitative PCR and western blot analysis were performed to detect the expression levels of Ubiquitin-specific peptidase 46 (USP46) and Pumilio 2 (PUM2) in OC. Cell viability and apoptosis were evaluated by Cell Counting Kit-8 assay and flow cytometry, respectively. The association between USP46 and PUM2 was assessed by RNA immunoprecipitation. The results of the present study revealed that the expression levels of USP46 which is associated with tumor progression, was downregulated, while PUM2 expression levels were upregulated in cisplatin (DDP)-resistant OC cells and patient tissues. The downregulation of USP46 expression levels in SKOV3 cells significantly inhibited cell apoptosis and increased cell viability. In SKOV3/DDP cells, the upregulation of USP46 expression levels notably suppressed cell viability and increased cell apoptosis. The results of the RNA immunoprecipitation chip assay demonstrated that PUM2 bound to USP46 and regulated its expression. Furthermore, following the knockdown of USP46 expression, the mRNA and protein expression levels of the cell apoptosis-related protein, Bcl-2, were upregulated, whereas the expression levels of caspase-3, caspase-9 and Bax were significantly downregulated. In addition, phosphorylated AKT expression levels were notably upregulated. Following the overexpression of USP46 in SKOV3/DDP cells, the opposite trends were observed. In SKOV3 cells, the knockdown of PUM2 could reverse the DDP resistance induced by small interfering RNA-USP46 as the expression levels of Bcl-2 were downregulated whereas those of caspase-3, caspase-9 and Bax were upregulated compared with the small interfering-USP46 group. Similarly, in SKOV3/DDP cells, the overexpression of PUM2 could reverse DDP sensitivity induced by the overexpression of USP46. In conclusion, the findings of the present study suggested that the downregulation of USP46 expression levels may promote DDP resistance in OC, which may be regulated by PUM2. Therefore, targeting PUM2/USP46 may be an effective way to reverse DDP resistance in OC.

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Section: Discussionmentioning

confidence: 99%

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Xu¹,

Zhang²,

Li³

2021

Mol Med Rep

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“…Several studies have reported that CD44 and CD117 are two stem cell markers in ovarian cancer, and that CD44 + CD117 + cancer cells present with a powerful survival ability and tumorigenic capability ( 23 , 24 ). In ovarian cancer cells, the overexpression of miR-199a could significantly inhibit CD44 expression and attenuate multidrug resistance and tumorigenicity ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Chemokine CCL20 promotes the paclitaxel resistance of CD44⁺CD117⁺ cells via the Notch1 signaling pathway in ovarian cancer

Chen

et al. 2021

Mol Med Rep

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Studies have found that C-C motif chemokine ligand 20 (CCL20)/C-C motif chemokine receptor 6 (CCR6)/notch receptor 1 (Notch1) signaling serves an important role in various diseases, but its role and mechanism in ovarian cancer remains to be elucidated. The aim of the present study was to investigate the underlying mechanism of CCL20/CCR6/Notch1 signaling in paclitaxel (PTX) resistance of a CD44 + CD117 + subgroup of cells in ovarian cancer. The CD44 + CD117 + cells were isolated from SKOV3 cells, followed by determination of the PTX resistance and the CCR6/Notch1 axis. Notch1 was silenced in the CD44 + CD117 + subgroup and these cells were treated with CCL20, followed by examination of PTX resistance and the CCR6/Notch1 axis. Furthermore, in nude mice, CD44 + CD117 + and CD44 -CD117cells were used to establish the xenograft model and cells were treated with PTX and/or CCL20, followed by proliferation, apoptosis, reactive oxygen species (ROS) and mechanism analyses. Higher expression levels of Oct4, CCR6, Notch1 and ATP binding cassette subfamily G member 1 (ABCG1), increased sphere formation ability, IC 50 and proliferative ability, as well as lower ROS levels and apoptosis were observed in CD44 + CD117 + cells compared with the CD44 -CD117cells. It was found that CCL20 could significantly increase the expression levels of Oct4, CCR6, Notch1 and ABCG1, enhance the IC 50 , sphere formation ability and proliferation, as well as decrease the ROS and apoptosis levels in the CD44 + CD117 + cells. However, Notch1 knockdown could markedly reverse these changes. Moreover, CCL20 could significantly increase the proliferation and expression levels of Oct4, CCR6, Notch1 and ABCG1 in the CD44 + CD117 + groups compared with the CD44 -CD117groups. After treatment with PTX, apoptosis and ROS levels were decreased in the CD44 + CD117 + groups compared with the CD44 -CD117groups. Collectively, the present results demonstrated that, via the Notch1 pathway, CCL20/CCR6 may promote the stemness and PTX resistance of CD44 + CD117 + cells in ovarian cancer.

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“…Using the correlation between MYB and OC to evaluate the prognosis and explore potential therapeutic targets has attracted much attention [33][34][35].But,the study found that MYB-77867-ES for OC prognosis is favorable AS event. The results suggest that splicing may change the role of genes.AGO2 is a Protein Coding gene, which have effect on cervical cancer, breast cancer and other tumors [36][37][38].AGO2 fail in our study it happened happened AGO2-85285-ES is bene cial to the prognosis of OC, but in other studies, AGO2 can have opposite effects on the prognosis of OC through different pathways [39][40][41].Few studies have been done on SERF1B and ZNF630,we get SERF1B-72406-RI ZNF630-88949-AP close contact with OC, they may be effective prognostic biomarkers and therapeutic targets.Among the remaining results, there are many previous studies on CD44 gene.As a non-kinase transmembrane receptor,CD44 can be used as an effective biomarker to predict the prognosis of OC and negatively affect the outcome of OC [42].CD44 plays a multi-functional role, such as related to cancer stem cells and tumor-associated macrophages, leading to drug resistance of recurrent chemotherapy drugs in OC. It is expected to further dig out effective therapeutic targets to reduce the recurrence rate and drug resistance rate of OC [43,44].It interacts with STAT3 to affect a series of processes such as angiogenesis and immune regulation in OC [45][46][47].CD44 and STAT3 work together on OC in a variety of way,which can provide various ideas for OC treatment.…”

Section: Discussionmentioning

confidence: 99%

Systematic Analysis of the Relationship Between Ovarian Cancer Prognosis and Alternative Splicing

Zhang

Zou

Deng

et al. 2021

Preprint

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Background: Ovarian cancer(OC) is the gynecological tumor with the highest mortality rate, effective biomarkers are of great significance in improving its prognosis. In recent years, there have been many studies on alternative splicing (AS) events, and the role of AS events in tumor has become a focus of attention.Methods: Data were downloaded from the TCGA database and Univariate Cox regression analysis was performed to determine AS events associated with OC prognosis. Eight prognostic models of OC were constructed in R package, and the accuracy of the models were evaluated by the time-dependent receiver operating characteristic (ROC) curves. Eight types of survival curves were drawn to evaluate the differences between the high and low risk groups. Independent prognostic factors of OC were analyzed by single factor independent analysis and multi-factor independent prognostic analysis. Again, Univariate Cox regression analysis was used to analyze the relationship between splicing factors(SF) and AS events, and Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis were performed on OS-related SFs to understand the pathways.Results: Univariate Cox regression analysis showed that among the 15,278 genes, there were 31,286 overall survival (OS) related AS events, among which 1524 AS events were significantly correlated with OS. The area under the time-dependent receiver operating characteristic curve (AUC) of AT and ME were the largest and the RI was the smallest ,which were 0.757 and 0.68 respectively. The constructed models have good value for the prognosis assessment of OC patients. Among the eight survival curves, AP was the most significant difference between the high and low risk groups, with a P value of 1.61e−1.The results of single factor independent analysis and multi-factor independent prognostic analysis showed that risk score calculated by the model and age could be used as independent risk factors. According to univariate COX regression analysis ,109 SFs were correlated with AS events and adjusted in two ways: positive and negative.Conclusions: SFs and AS events can directly or indirectly affect the prognosis of OC patients. It is very important to find effective prognostic markers to improve the survival rate of OC.

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CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

Cited by 50 publications

References 255 publications

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Chemokine CCL20 promotes the paclitaxel resistance of CD44⁺CD117⁺ cells via the Notch1 signaling pathway in ovarian cancer

Systematic Analysis of the Relationship Between Ovarian Cancer Prognosis and Alternative Splicing

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CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

Cited by 50 publications

References 255 publications

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Chemokine CCL20 promotes the paclitaxel resistance of CD44+CD117+ cells via the Notch1 signaling pathway in ovarian cancer

Systematic Analysis of the Relationship Between Ovarian Cancer Prognosis and Alternative Splicing

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Chemokine CCL20 promotes the paclitaxel resistance of CD44⁺CD117⁺ cells via the Notch1 signaling pathway in ovarian cancer