HOTTIP-miR-205-ZEB2 Axis Confers Cisplatin Resistance to Ovarian Cancer Cells

Dong, Yujie; Wei, Feng; Yan, Li

doi:10.3389/fcell.2021.707424

Cited by 14 publications

(12 citation statements)

References 49 publications

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“…Notably, a 7-fold increase in the IC 50 of DDP was observed for SKOV3/DDP cells compared with that for wild-type cells ( Figure 1D ), confirming the successful establishment of DDP-resistant OC cells. A2780 and A2780/DDP cells are well-known paired DDP-sensitive and DDP-resistant cell lines ( 29 ). Compared with A2780 cells, A2780/DDP cells had a 5-fold increase in DDP resistance ( Figure 1E ).…”

Section: Resultsmentioning

confidence: 99%

Hedgehog−Gli2 Signaling Promotes Chemoresistance in Ovarian Cancer Cells by Regulating MDR1

Wang

Wei

et al. 2022

Front. Oncol.

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BackgroundCisplatin (DDP) resistance remains a key challenge in improving the clinical outcome of patients with ovarian cancer (OC). Gli2 overexpression can lead to DDP resistance in OC cells, but the specific underlying regulatory mechanism remains unclear. The membrane transporter encoding gene MDR1 positively regulates chemotherapy resistance in various cancer types. We evaluated MDR1 as a potential Gli2 downstream target and the contribution of the Gli2/MDR1 axis in promoting DDP resistance in OC cells.MethodsTo generate drug-resistant SKOV3/DDP cells, SKOV3 cells were grown for six months under continuous induction wherein the DDP concentration was steadily increased. Gli2 expression in OC cells with varying DDP sensitivities was detected using western blot. Cell counting kit-8 assays were used to assess the DDP sensitivity of SKOV3, SKOV3/DDP, A2780, and A2780/DDP cells and reversal of DDP resistance in SKOV3/DDP and A2780/DDP cells. Cell proliferation was analyzed using 5-ethynyl-2′-deoxyuridine (EdU) incorporation assays. The transcriptional regulation of MDR1 by Gli2 was determined using luciferase reporter assays. Finally, xenograft OC tumors were generated in nude mice, which were then treated with intraperitoneal DDP or phosphate-buffered saline (PBS) injections to investigate if Gli2 affected DDP resistance in OC in vivo.ResultsDDP-resistant SKOV3/DDP and A2780/DDP cells showed higher expression of Gli2 and MDR1 as compared with that in DDP-sensitive OC cells. Gli2 knockdown in SKOV3/DDP cells significantly reduced MDR1 expression, whereas it increased DNA damage, thereby sensitizing OC cells to DDP. Similar results were obtained after targeting Gli2 expression with the Gli-antagonist 61 inhibitor (GANT61) in SKOV3/DDP and A2780/DDP cells. In cells stably overexpressing Gli2, treatment with gradient concentrations of verapamil, an MDR1 inhibitor, significantly inhibited MDR1 expression. Our findings indicate that downregulation of MDR1 expression may reverse OC cell resistance to DDP. Moreover, dual-luciferase reporter gene assays confirmed that MDR1 is a direct downstream target of Gli2, with Gli2 positively regulating MDR1 expression. Finally, subcutaneous xenotransplantation in nude mice demonstrated that Gli2 plays a key role in regulating OC drug resistance.ConclusionsWe identified a mechanism by which Hedgehog-Gli signaling regulates OC chemoresistance by modulating MDR1 expression. Hence, Gli2 and MDR1 are potential biomarkers and therapeutic targets in patients with chemoresistant OC.

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Section: Resultsmentioning

confidence: 99%

Hedgehog−Gli2 Signaling Promotes Chemoresistance in Ovarian Cancer Cells by Regulating MDR1

Wang

Wei

et al. 2022

Front. Oncol.

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“…Downregulation of HOTTIP turns WNT/β-catenin signaling inactive, improving anti-prostate cancer effects of cisplatin [152]. Similarly, HOTTIP enhances stemness by attenuating miR-205 effects and confers resistance to cisplatin in ovarian cancer [153].…”

Section: Hottipmentioning

confidence: 99%

Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers

Yun

Choi

Son

et al. 2022

IJMS

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Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell–cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes.

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“…There was a significant HOTTIP up regulation in DDP resistant ovarian tumor cells. HOTTIP increased DDP resistance in ovarian tumor cells by miR-205 sponging and ZEB2 up regulation [ 75 ].…”

Section: Main Textmentioning

confidence: 99%

“… Zhang [ 74 ] 2019 miR-132 China BMI1 SKOV3 cell line Increased DDP sensitivity. Dong [ 75 ] 2021 miR-205 China ZEB2 A2780 and SKOV3 cell lines Increased DDP sensitivity. Liu [ 76 ] 2014 miR-101 China EZH2 70 patients A2780 and SKOV3 cell lines Increased DDP sensitivity.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs as the critical regulators of Cisplatin resistance in ovarian cancer cells

Moghbeli

2021

J Ovarian Res

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Background Ovarian cancer (OC) is one of the leading causes of cancer related deaths among women. Due to the asymptomatic tumor progression and lack of efficient screening methods, majority of OC patients are diagnosed in advanced tumor stages. A combination of surgical resection and platinum based-therapy is the common treatment option for advanced OC patients. However, tumor relapse is observed in about 70% of cases due to the treatment failure. Cisplatin is widely used as an efficient first-line treatment option for OC; however cisplatin resistance is observed in a noticeable ratio of cases. Regarding, the severe cisplatin side effects, it is required to clarify the molecular biology of cisplatin resistance to improve the clinical outcomes of OC patients. Cisplatin resistance in OC is associated with abnormal drug transportation, increased detoxification, abnormal apoptosis, and abnormal DNA repair ability. MicroRNAs (miRNAs) are critical factors involved in cell proliferation, apoptosis, and chemo resistance. MiRNAs as non-invasive and more stable factors compared with mRNAs, can be introduced as efficient markers of cisplatin response in OC patients. Main body In present review, we have summarized all of the miRNAs that have been associated with cisplatin resistance in OC. We also categorized the miRNAs based on their targets to clarify their probable molecular mechanisms during cisplatin resistance in ovarian tumor cells. Conclusions It was observed that miRNAs mainly exert their role in cisplatin response through regulation of apoptosis, signaling pathways, and transcription factors in OC cells. This review highlighted the miRNAs as important regulators of cisplatin response in ovarian tumor cells. Moreover, present review paves the way of suggesting a non-invasive panel of prediction markers for cisplatin response among OC patients.

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HOTTIP-miR-205-ZEB2 Axis Confers Cisplatin Resistance to Ovarian Cancer Cells

Cited by 14 publications

References 49 publications

Hedgehog−Gli2 Signaling Promotes Chemoresistance in Ovarian Cancer Cells by Regulating MDR1

Hedgehog−Gli2 Signaling Promotes Chemoresistance in Ovarian Cancer Cells by Regulating MDR1

Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers

MicroRNAs as the critical regulators of Cisplatin resistance in ovarian cancer cells

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