MicroRNA-200b and -301 are associated with gemcitabine response as biomarkers in pancreatic carcinoma cells

Funamizu, Naotake; Lacy, Curtis; Kamada, Minori; Yanaga, Katsuhiko; Manome, Yoshinobu

doi:10.3892/ijo.2019.4676

Cited by 15 publications

(19 citation statements)

References 47 publications

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“…Based on pilot studies, we have chosen LD20 gemcitabine concentration, which proved to be 200-times higher for Panc1 than for Capan1, which is in line with the higher GEM resistance of Panc1 cell line [29]. Similar to our earlier published results [22], a 60-min mEHT-treatment induced significant apoptosis in FIGURE 5 | Cell cycle analysis for Capan1 and Panc1 cell lines 24 and 48 h after mEHT treatment.…”

Section: Discussionsupporting

confidence: 57%

Modulated Electro-Hyperthermia Supports the Effect of Gemcitabine Both in Sensitive and Resistant Pancreas Adenocarcinoma Cell Lines

Forika¹,

Kiss²,

Petővári³

et al. 2021

Pathol. Oncol. Res.

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The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is frequently associated to high treatment resistance. Gemcitabine (GEM) alone or in combination is the most used chemotherapy for unresecable PDACs. Here we studied whether modulated electro-hyperthermia (mEHT), a non-invasive complementary treatment, can support the effect of GEM on PDAC cells in vitro. The LD20 for the GEM-resistant Panc1 cells proved to be 200× higher than for the drug-sensitive Capan1. The mEHT alone caused significant apoptosis in Capan1 cultures as confirmed by the elevated SubG1 phase cell fraction and increased number of cleaved Caspase-3 positive cells 48 h after treatment, with an additive effect when GEM was used after hyperthermia. These were accompanied by reduced number of G1, S, and G2/M phase cells and elevated expression of the cyclin-dependent kinase inhibitor p21waf1 protein. In GEM-resistant Panc1 cells, an initial apoptosis was detected by flow cytometry 24 h after mEHT ± GEM treatment, which however diminished by 48 h at persistent number of cleaved Caspase-3 positive tumor cells. Though GEM monotherapy reduced the number of tumor progenitor colonies in Capan1 cell line, an additive colony inhibitory effect of mEHT was observed after mEHT + GEM treatment. The heat shock induced Hsp27 and Hsp70 proteins, which are known to sensitize PDAC cells to GEM were upregulated in both Capan1 and Panc1 cells 24 h after mEHT treatment. The level of E-Cadherin, a cell adhesion molecule, increased in Capan1 cells after mEHT + GEM treatment. In conclusion, in GEM-sensitive PDAC cells mEHT treatment alone induced cell death and cell cycle inhibition and improved GEM efficiency in combination, which effects were milder and short-term up to 24 h in the GEM-resistant Panc1 cells. Our data further support the inclusion of hyperthermia, in particular of mEHT, into the traditional oncotherapy regimens of PDAC.

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Section: Discussionsupporting

confidence: 57%

Modulated Electro-Hyperthermia Supports the Effect of Gemcitabine Both in Sensitive and Resistant Pancreas Adenocarcinoma Cell Lines

Forika¹,

Kiss²,

Petővári³

et al. 2021

Pathol. Oncol. Res.

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“…Wang et al validated the role of miR-30a in PC sensitization to gemcitabine (10). Another study reported that gemcitabineresistant cells exhibited upregulated miR-301 expression and downregulated gemcitabine-induced apoptosis (11).…”

Section: Introductionmentioning

confidence: 97%

Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4+ T cells

Zhang

Huang

et al. 2020

Ann Transl Med

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Background: To identify key microRNAs (miRNAs) and their target mRNAs related to gemcitabineresistant pancreatic cancer (PC) and investigate the association between gemcitabine-resistant-related miRNAs and mRNAs and immune infiltration.Methods: Expression profiles of miRNAs and mRNAs were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed miRNAs and mRNAs (referred to as "DEmiRNAs" and "DEmRNAs", respectively) were distinguished between gemcitabine-resistant PC cells and its parental cells. The DEmRNAs targeted by the DEmiRNAs were retrieved using miRDB, microT, and Targetscan. Furthermore, GO and KEGG pathway enrichment analysis and GSEA were performed. The Kaplan-Meier plotter was used to analyze the prognosis of key DEmiRNAs and DEmRNAs on PC patients. The relationship between the key DEmRNAs and tumor-infiltrating immune cells in PC was investigated using CIBERSORT method using the LM22 signature as reference. Key infiltrating immune cells were further analyzed for the associations with prognosis of TCGA PAAD patients.Results: Four DEmiRNAs, including hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p, and hsa-miR-584-5p, were identified to target seven DEmRNAs, including MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6, individually, in gemcitabine-resistant PC cells versus parental cells. Gemcitabineresistant PC cells were enriched in proteasome-related, immune-related, and memory CD4 + T cell-related pathways, indicating a gemcitabine therapeutic effect on PC cells. All four DEmiRNAs and almost all DEmRNAs had an impact on the prognosis of PC patients. All seven DEmRNAs had remarkable effects on CD4 + memory T cells, which were affected by the gemcitabine therapeutic effect. Effector memory CD4 + T cells rather than central memory CD4 + T cells predicted a good prognosis according to the TCGA PAAD dataset.Conclusions: Gemcitabine resistance can alter the fraction of memory CD4 + T cells via hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p and hsa-miR-584-5p targeted MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6 network in PC.

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“…Gemcitabine is widely used in advanced pancreatic carcinoma. MiR-200b and miR-125a-3p are revealed to improve chemosensitivity via reversing EMT [131,132], while miR-301 mediates gemcitabine resistance and induces EMT through downregulating cadherin 1 in pancreatic tumor cell lines [131]. In OS, DDP resistance can be alleviated by miR-340 via targeting ZEB1 [133], and miR-233 via forming the miR-233/Hsp70/JNK/JUN/ miR-233 feedback loop [134].…”

Section: Other Cancersmentioning

confidence: 99%

Role of non-coding RNAs and RNA modifiers in cancer therapy resistance

et al. 2020

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As the standard treatments for cancer, chemotherapy and radiotherapy have been widely applied to clinical practice worldwide. However, the resistance to cancer therapies is a major challenge in clinics and scientific research, resulting in tumor recurrence and metastasis. The mechanisms of therapy resistance are complicated and result from multiple factors. Among them, non-coding RNAs (ncRNAs), along with their modifiers, have been investigated to play key roles in regulating tumor development and mediating therapy resistance within various cancers, such as hepatocellular carcinoma, breast cancer, lung cancer, gastric cancer, etc. In this review, we attempt to elucidate the mechanisms underlying ncRNA/modifier-modulated resistance to chemotherapy and radiotherapy, providing some therapeutic potential points for future cancer treatment.

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MicroRNA-200b and -301 are associated with gemcitabine response as biomarkers in pancreatic carcinoma cells

Cited by 15 publications

References 47 publications

Modulated Electro-Hyperthermia Supports the Effect of Gemcitabine Both in Sensitive and Resistant Pancreas Adenocarcinoma Cell Lines

Modulated Electro-Hyperthermia Supports the Effect of Gemcitabine Both in Sensitive and Resistant Pancreas Adenocarcinoma Cell Lines

Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4+ T cells

Role of non-coding RNAs and RNA modifiers in cancer therapy resistance

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