chemotherapy resistance
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2022 ◽  
Vol 12 (4) ◽  
pp. 763-769
Liang Yu ◽  
Sheng Zhang ◽  
Wei He

microRNA-136 can inhibit the proliferating activity of malignant cells and also participate in chemotherapy resistance of colorectal cancer via modulating HDAC1. This study assessed miR-136’s effect on NSCLC cell proliferation and underlying mechanisms. Tumor tissues and paracancerous tissues from NSCLC patients were collected to measure miR-136 and HDAC1 level. Cells were transfected with miR-136-mimics, miR-136-inhibitors or miR-136 mimics+HDAC1-OE followed by analysis of cell viability and apoptosis by CCK-8 method and flow cytometry, phosphorylation of Jak2/STAT3 by western blot. miR-136 was significantly downregulated in tumor tissues and NSCLC cells, accompanied by upregulated HDAC1. miR-136 overexpression suppressed HDAC1 expression, retarded phosphorylation and activation of Jak2/STAT3 signaling, reduced NSCLC cell viability and enhanced apoptosis. In addition, co-transfection of miR-136-mimics and HDAC1-OE reversed the inhibitory effects of miR-136 on NSCLC cells. In conclusion, miR-136 is reduced and HDAC1 is increased in NSCLC and miR-136 overexpression inhibited NSCLC cell proliferation and increased apoptosis possibly through regulating HDAC1/Jak2/STAT3 signal pathway, indicating that miR-136 might be a novel target for the treatment of NSCLC.

2022 ◽  
Vol 12 (2) ◽  
pp. 258-264
ZhongXin Wu ◽  
Tianyi Huang

miR-168-5p is indicated as an upstream effector of the tumor suppressor signal pathway in ovarian cancer and bladder cancer, but the role in gastric cancer (GC) remains unknown. This study aims to reveal the expression and significance of miR-168-5p in GC. RT-qPCR analysis was used to detect the expression of miR-168-5p in GC tissues and plasma, and the relationship of miR-168-5p and CCND1 was evaluated. GC cells were co-cultured with BMSCs or transfected with miR-168-5p mimic. CCK-8 assay and flow cytometry were conducted to assess the effect of miR-168-5p in GC and the interaction between BMSCs and cancer cell progression. Animal experiment was established to explore the in vivo effect of miR-168-5p. miR-168-5p is poorly expressed in gastric cancer cells and the plasma of patients with gastric cancer. BMSC co-culture is similar to miR-168-5p mimic induced miR-168-5p expression increase. miR-168-5p overexpression decreased the proliferative, invasive and migratory capacities of GC cells, and promoted apoptosis. Mechanically, miR-168-5p targeted and decreased the expression of CCND1. Additionally, the low miR-168-5p expression in GC was closely related to poor prognosis and malignant transformation. BMSC exosomes carrying miR-168-5p suppress cell progression in GC when inhibiting the expression of CCND1 and P glycoprotein, which indicates potential diagnostic and prognostic value of miR-168-5p and helps the development of miR-168-5p-based treatment for drug-resistant GC.

2022 ◽  
Vol 15 (1) ◽  
Lili Zhong ◽  
Xiumin Liu ◽  
Lixing Wang ◽  
Yu Liu ◽  
Duohan Zhang ◽  

Abstract Objective High-grade serous ovarian cancer (HGSOC) is an aggressive gynaecological malignancy and associated with poor prognosis. Here we examined the effects of miR-625-3p on proliferation, treatment, migration and invasion in HGSOC. Methods The proliferation of HGSOC cells was evaluated by MTT assay. Transwell assay was performed to examine migration and matrigel assay were used to assess invasion. The effect of miR-625-3p on cisplatin-induced apoptosis was investigated by Caspase-Glo3/7 assay. The dual-luciferase reporter assay was carried out to confirm the potential binding site. Results Overexpression of miR-625-3p promoted proliferation, and increased migration and invasion in HGSOC cells. MiR-625-3p significantly inhibited cisplatin sensitivity in HGSOC cells. Meanwhile, miR-625-3p decreased cisplatin-induced apoptosis by regulation of BAX and Bcl-2 expression. Furthermore, aberrant expression of miR-625-3p changed PTEN expression by directly binding to 3’UTR of PTEN. Further study showed miR-625-3p expression was higher in human HGSOC tissue than normal ovarian tissues and associated with higher clinical stage. Conclusions miR-625-3p promotes HGSOC growth, involves chemotherapy resistance and might serve as a potential biomarker to predict chemotherapy response and prognosis in HGSOC.

2022 ◽  
Vol 12 ◽  
Bingqing Shang ◽  
Chuanzhen Cao ◽  
Weixing Jiang ◽  
Hongzhe Shi ◽  
Xingang Bi ◽  

BackgroundTesticular sex cord stromal tumours (TSCSTs) are rare, with few studies focusing on the metastatic TSCST prognosis. The value of treatments, including radical orchiectomy (RO) and retroperitoneal lymph node dissection (RPLND), in preventing metastasis is controversial. Additionally, metastatic TSCSTs are resistant to chemotherapy. We aimed to assess the effectiveness and safety of immunotherapy in metastatic TSCSTs after first-line chemotherapy.MethodsWe retrospectively screened patients with testicular tumours undergoing testis surgery between January 2005 and January 2019. Patients with TSCSTs who had undergone testis-sparing surgery (TSS) or RO were identified. The malignant type was defined as metastasis confirmed by pathology. Treatment responses, progression-free survival (PFS), overall survival (OS) and safety were analysed.ResultsAmong the 494 testicular tumour patients who received TSS or RO, 11 (2.2%) patients with histologically proven TSCSTs were identified. At the last follow-up, 7 patients survived without tumours, and 4 patients developed metastasis and received first-line cisplatin-based chemotherapy, with 1 of them achieving an objective response. Their PFS times were 1.5, 2.2, 9.0, and 17.0 months, respectively. Two patients received immune checkpoint inhibitors (ICIs) after developing chemotherapy resistance and achieved a partial response up to the last follow-up; one of them experienced Grade 1 adverse events, and the other experienced Grade 2 adverse events during immunotherapy. The median OS time of the 4 patients with metastatic TSCSTs was 32 months.ConclusionsTSCSTs are rare, and most are benign with a good prognosis. ICIs represent a promising option for improving clinical outcomes in metastatic TSCSTs.

2022 ◽  
Vol 8 (1) ◽  
Zhongrui Li ◽  
Lan Zhang ◽  
Dongrui Liu ◽  
Zhanghui Yang ◽  
Di Xuan ◽  

AbstractChemotherapy resistance of tumor cells causes failure in anti-tumor therapies. Recently, N-terminal regulator of chromatin condensation 1 methyltransferase (NRMT) is abnormally expressed in different cancers. Hence, we speculate that NRMT may pay a crucial role in the development of chemosensitivity in retinoblastoma. We characterized the upregulation of NRMT in the developed cisplatin (CDDP)-resistant retinoblastoma cell line relative to parental cells. Loss-of-function experiments demonstrated that NRMT silencing enhanced chemosensitivity of retinoblastoma cells to CDDP. Next, NRMT was identified to enrich histone-H3 lysine 4 trimethylation in the promoter of centromere protein A (CENPA) by chromatin immunoprecipitation assay. Rescue experiments suggested that CENPA reduced chemosensitivity by increasing the viability and proliferation and reducing apoptosis of CDDP-resistant retinoblastoma cells, which was reversed by NRMT. Subsequently, CENPA was witnessed to induce the transcription of Myc and to elevate the expression of B cell lymphoma-2. At last, in vivo experiments confirmed the promotive effect of NRMT knockdown on chemosensitivity of retinoblastoma cells to CDDP in tumor-bearing mice. Taken together, NRMT is an inhibitor of chemosensitivity in retinoblastoma. Those findings shed new light on NRMT-targeted therapies for retinoblastoma.

2022 ◽  
Vol 11 ◽  
Qian Wang ◽  
Xin Wei ◽  
Lanyan Hu ◽  
Lingling Zhuang ◽  
Hong Zhang ◽  

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.

2022 ◽  
Jeff Rytlewski ◽  
Qierra R. Brockman ◽  
Rebecca D. Dodd ◽  
Mohammed Milhem ◽  
Varun Monga

Sarcomas are a class of rare malignancies of mesenchymal origin with a heterogeneous histological spectrum. They are classically associated with poor outcomes, especially once metastasized. A path to improving clinical outcomes may be made through modifying the epigenome, where a variety of sarcomas demonstrate changes that contribute to their oncogenic phenotypes. This Perspective article identifies and describes changes in the sarcoma genome, while discussing specific epigenetic changes and their effect on clinical outcomes. Clinical attempts at modulating epigenetics in sarcoma are reviewed, as well as potential implications of these studies. Epigenetic targets to reverse and delay chemotherapy resistance are discussed. Future directions with primary next steps are proposed to invigorate the current understanding of epigenetic biomarkers to enact targeted therapies to epigenetic phenotypes of sarcoma subtypes. Modifications to prior studies, as well as proposed clinical steps, are also addressed.

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 97
Maria Gagliardi ◽  
Ana Tari Ashizawa

The B-cell lymphoma 2 (Bcl-2) family, comprised of pro- and anti-apoptotic proteins, regulates the delicate balance between programmed cell death and cell survival. The Bcl-2 family is essential in the maintenance of tissue homeostasis, but also a key culprit in tumorigenesis. Anti-apoptotic Bcl-2, the founding member of this family, was discovered due to its dysregulated expression in non-Hodgkin’s lymphoma. Bcl-2 is a central protagonist in a wide range of human cancers, promoting cell survival, angiogenesis and chemotherapy resistance; this has prompted the development of Bcl-2-targeting drugs. Antisense oligonucleotides (ASO) are highly specific nucleic acid polymers used to modulate target gene expression. Over the past 25 years several Bcl-2 ASO have been developed in preclinical studies and explored in clinical trials. This review will describe the history and development of Bcl-2-targeted ASO; from initial attempts, optimizations, clinical trials undertaken and the promising candidates at hand.

2021 ◽  
Vol 23 (1) ◽  
pp. 450
Rocío Jiménez-Guerrero ◽  
Alejandro Belmonte-Fernández ◽  
M. Luz Flores ◽  
Mónica González-Moreno ◽  
Begoña Pérez-Valderrama ◽  

The Wnt/β-catenin pathway plays an important role in tumor progression and chemotherapy resistance and seems to be essential for the maintenance of cancer stem cells (CSC) in several tumor types. However, the interplay of these factors has not been fully addressed in bladder cancer. Here, our goal was to analyze the role of the Wnt/β-catenin pathway in paclitaxel resistance and to study the therapeutic efficacy of its inhibition in bladder cancer cells, as well as to determine its influence in the maintenance of the CSC-like phenotype in bladder cancer. Our results show that paclitaxel-resistant HT1197 cells have hyperactivation of the Wnt/β-catenin pathway and increased CSC-like properties compared with paclitaxel-sensitive 5637 cells. Paclitaxel sensitivity diminishes in 5637 cells after β-catenin overexpression or when they are grown as tumorspheres, enriched for the CSC-like phenotype. Additionally, downregulation of β-catenin or inhibition with XAV939 sensitizes HT1197 cells to paclitaxel. Moreover, a subset of muscle-invasive bladder carcinomas shows aberrant expression of β-catenin that associates with positive expression of the CSC marker ALDH1A1. In conclusion, we demonstrate that Wnt/β-catenin signaling contributes to paclitaxel resistance in bladder cancer cells with CSC-like properties.

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 24
Konstantina Panoutsopoulou ◽  
Tobias Dreyer ◽  
Julia Dorn ◽  
Eva Obermayr ◽  
Sven Mahner ◽  

Epithelial ovarian cancer (EOC) remains a highly-lethal gynecological malignancy, characterized by frequent recurrence, chemotherapy resistance and poor 5-year survival. Identifying novel predictive molecular markers remains an overdue challenge in the disease’s clinical management. Herein, in silico analysis of TCGA-OV highlighted the tRNA-derived internal fragment (i-tRF-GlyGCC) among the most abundant tRFs in ovarian tumors, while target prediction and gene ontology (GO) enrichment analysis predicted its implication in key biological processes. Thereafter, i-tRF-GlyGCC levels were quantified in a screening EOC (n = 98) and an institutionally-independent serous ovarian cancer (SOC) validation cohort (n = 100, OVCAD multicenter study). Disease progression and patient death were used as clinical endpoints for the survival analysis. Internal validation was performed by bootstrap analysis and the clinical net benefit was estimated by decision curve analysis. The analysis highlighted the significant association of i-tRF-GlyGCC with advanced FIGO stages, suboptimal debulking and most importantly, with early progression and poor overall survival of EOC patients. The OVCAD validation cohort corroborated the unfavorable predictive value of i-tRF-GlyGCC in EOC. Ultimately, evaluation of i-tRF-GlyGCC with the established/clinically used prognostic markers offered superior patient risk-stratification and enhanced clinical benefit in EOC prognosis. In conclusion, i-tRF-GlyGCC assessment could aid towards personalized prognosis and support precision medicine decisions in EOC.

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