miR‑375/Yes‑associated protein axis regulates IL‑6 and TGF‑β expression, which is involved in the cisplatin‑induced resistance of liver cancer cells

Yu, Kanru; Li, Hao; Jiang, Zhongyi; Hsu, Han-Jen; Hsu, Hsing-Chun; Zhang, Yumei; Wang, Kunwei

doi:10.3892/or.2021.8112

Cited by 4 publications

(5 citation statements)

References 46 publications

(48 reference statements)

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“…The evaluation of miRNA expression among these chemoresistant cell lines demonstrated a positive association with miR-375 expression, which may be one of the first studies to validate this result in a commercially available cell line [ 20 , 21 , 22 ]. Studies of miR-375 among liver cancers have demonstrated that this resistance may function through modulation of Non-SMC Condensin II Complex Subunit G2 (NCAPG2), Interleukin 6 (IL-6) and Transforming growth factor-beta (TGF-β) [ 34 , 35 ]. Additional research studies of osteosarcoma have demonstrated that miR-375 may function through interactions with Autophagy related gene 2B (ATG2B) and Myeloid leukemia cell differentiation protein (Mcl-1) [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Chemotherapeutic Drug Resistance Associated with Differential miRNA Expression of miR-375 and miR-27 among Oral Cancer Cell Lines

Huni

Cheung²,

Sullivan³

et al. 2023

IJMS

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Recent advances have suggested that non-coding miRNAs (such as miR-21, miR-27, miR-145, miR-155, miR-365, miR-375 and miR-494) may be involved in multiple aspects of oral cancer chemotherapeutic responsiveness. This study evaluated whether these specific miRNAs are correlated with oral cancer responsiveness to chemotherapies, including Paclitaxel, Cisplatin and Fluorouracil (5FU). Commercially available and well-characterized oral squamous cell carcinoma cell lines (SCC4, SCC9, SCC15, SCC25 and CAL27) revealed differing resistance and chemosensitivity to these agents—with SCC9 and SCC25 demonstrating the most resistance to all chemotherapeutic agents. SCC9 and SCC25 were also the only cell lines that expressed miR-375, and were the only cell lines that did not express miR-27. In addition, the expression of miR-375 was associated with the upregulation of Rearranged L-myc fusion (RLF) and the downregulation of Centriolar protein B (POC1), whereas lack of miR-27 expression was associated with Nucleophosmin 1 (NPM1) expression. These data have revealed important regulatory pathways and mechanisms associated with oral cancer proliferation and resistance that must be explored in future studies of potential therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Chemotherapeutic Drug Resistance Associated with Differential miRNA Expression of miR-375 and miR-27 among Oral Cancer Cell Lines

Huni

Cheung²,

Sullivan³

et al. 2023

IJMS

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“…While its overexpression has been recognized to predominantly suppress all the core hallmarks of HCC [ 24 , 27 , 28 , 29 ]. The involvement of miR-375 in each of these hallmarks proceeds by directly targeting several important oncogenes-driven hepatocarcinogenesis like AEG-1 , MDR1 , P-gp , YAP1 , ATG7 , ATG14 , Bcl-2 , SIRT5 , and AKT/Ras [ 14 , 22 , 25 , 30 , 93 ]. Therefore, miR-375 has been confirmed to simultaneously play a strong anti-HCC effect.…”

Section: Discussionmentioning

confidence: 99%

“…The hypermethylation of CpG islands of miR-375 promoter has been reported as the main cause of its down-regulation [ 21 , 22 ]. Restoring the expression of miR-375 has been found to significantly repress the major hallmarks and all signaling networks of HCC, including cell growth, proliferation, anti-apoptosis, angiogenesis, glucose metabolism, autophagy, drug resistance, migration, and invasion [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. These suppressive effects of miR-375 are achieved via its multi-targeting key oncogenes involved in hepatocarcinogenic pathways.…”

Section: Introductionmentioning

confidence: 99%

Preparation and Optimization of MiR-375 Nano-Vector Using Two Novel Chitosan-Coated Nano-Structured Lipid Carriers as Gene Therapy for Hepatocellular Carcinoma

Soliman,

Wen,

Kandil

et al. 2024

Pharmaceutics

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Currently, there is still a lack of effective carriers with minimal side effects to deliver therapeutic miRNA. Thus, it is crucial to optimize novel drug delivery systems. MiR-375 has proven superior therapeutic potency in Hepatocellular carcinoma (HCC). The purpose of this study was to fabricate 2 novel and smart nano-carriers for the transportation efficiency of miR-375 in HCC cells and enhance its anti-tumor effects. We established the miR-375 construct through the pEGP- miR expression vector. Two nano-carriers of solid/liquid lipids and chitosan (CS) were strategically selected, prepared by high-speed homogenization, and optimized by varying nano-formulation factors. Thus, the two best nano-formulations were designated as F1 (0.5% CS) and F2 (1.5% CS) and were evaluated for miR-375 conjugation efficiency by gel electrophoresis and nanodrop assessment. Then, physio-chemical characteristics and stability tests for the miR-375 nano-plexes were all studied. Next, its efficiencies as replacement therapy in HepG2 cells have been assessed by fluorescence microscopy, flow cytometry, and cytotoxicity assay. The obtained data showed that two cationic nanostructured solid/liquid lipid carriers (NSLCs); F1 and F2 typically had the best physio-chemical parameters and long-term stability. Moreover, both F1 and F2 could form nano-plexes with the anionic miR-375 construct at weight ratios 250/1 and 50/1 via electrostatic interactions. In addition, these nano-plexes exhibited physical stability after three months and protected miR-375 from degradation in the presence of 50% fetal bovine serum (FBS). Furthermore, both nano-plexes could simultaneously deliver miR-375 into HepG2 cells and they ensure miR re-expression even in the presence of 50% FBS compared to free miR-375 (p-value < 0.001). Moreover, both F1 and F2 alone significantly exhibited minimal cytotoxicity in treated cells. In contrast, the nano-plexes significantly inhibited cell growth compared to free miR-375 or doxorubicin (DOX), respectively. More importantly, F2/miR-375 nano-plex exhibited more anti-proliferative activity in treated cells although its IC50 value was 55 times lower than DOX (p-value < 0.001). Collectively, our findings clearly emphasized the multifunctionality of the two CS-coated NSLCs in terms of their enhanced biocompatibility, biostability, conjugation, and transfection efficiency of therapeutic miR-375. Therefore, the NSLCs/miR-375 nano-plexes could serve as a novel and promising therapeutic strategy for HCC.

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“…The mRNA‒miRNA network was constructed to explore cisplatin resistance genes. ANXA1 [ 29 ], AREG [ 29 ], DUSP1 [ 30 ], DUSP8 [ 31 ], EGR1 [ 32 ], HRAS [ 33 ], IL6 [ 34 ], ILK [ 31 ], MAFB [ 35 ], MFAP5 [ 36 ], MSLN [ 37 ], NR4A1 [ 38 ], PINK1 [ 39 ], PRKCDBP [ 40 ], PTGER3 [ 41 ], SNCA [ 42 ], STIM1 [ 43 ] and TGFBI [ 44 ] have all been proven to be associated with cisplatin resistance. Immune environment analyses proved the connection of miR-675-3p to immune cells, and our data also showed that high expression of miR-675-3p might be related to decreased sensitivity to cisplatin.…”

Section: Discussionmentioning

confidence: 99%

Identification of upregulated exosomal miRNAs between A2780 and A2780/DDP human ovarian cancer cells by high-throughput sequencing

Liu

Zheng

et al. 2023

J Ovarian Res

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Exosomal miRNAs are known to play important roles in ovarian cancer and chemotherapeutic resistance. However, a systematic evaluation of characteristics of exosomal miRNAs involved in cisplatin resistance in ovarian cancer remains totally unclear. Exosomes (Exo-A2780, Exo-A2780/DDP) were extracted from cisplatin-sensitive cells (A2780) and cisplatin-resistant cells (A2780/DDP). Differential exosomal miRNA expression profiles were found by high-throughput sequencing (HTS). Target genes of the exo-miRNAs were predicted by using two online databases to increase the prediction accuracy. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were utilized to find biological relationships with chemoresistance. RT‒qPCR of three exosomal miRNAs was performed, and a protein‒protein interaction (PPI) network was established to identify the hub genes. The GDSC database was used to prove the association between hsa-miR-675-3p expression and the IC50 value. An integrated miRNA–mRNA network was constructed to predict miRNA–mRNA associations. The connection between hsa-miR-675-3p and ovarian cancer was discovered by immune microenvironment analyses. The upregulated exosomal miRNAs could regulate gene targets through signalling pathways such as the Ras, PI3K/Akt, Wnt, and ErbB pathways. GO and KEGG analyses indicated that the target genes were involved in protein binding, transcription regulator activity and DNA binding. The RT‒qPCR results were consistent with the HTS data, and the results of PPI network analysis suggested that FMR1 and CD86 were the hub genes. GDSC database analysis and construction of the integrated miRNA–mRNA network suggested that hsa-miR-675-3p was associated with drug resistance. Immune microenvironment analyses showed that hsa-miR-675-3p was crucial in ovarian cancer. The study suggested that exosomal hsa-miR-675-3p is a potential target for treating ovarian cancer and overcoming cisplatin resistance.

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miR‑375/Yes‑associated protein axis regulates IL‑6 and TGF‑β expression, which is involved in the cisplatin‑induced resistance of liver cancer cells

Cited by 4 publications

References 46 publications

Chemotherapeutic Drug Resistance Associated with Differential miRNA Expression of miR-375 and miR-27 among Oral Cancer Cell Lines

Chemotherapeutic Drug Resistance Associated with Differential miRNA Expression of miR-375 and miR-27 among Oral Cancer Cell Lines

Preparation and Optimization of MiR-375 Nano-Vector Using Two Novel Chitosan-Coated Nano-Structured Lipid Carriers as Gene Therapy for Hepatocellular Carcinoma

Identification of upregulated exosomal miRNAs between A2780 and A2780/DDP human ovarian cancer cells by high-throughput sequencing

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