CDDP-resistant Cell Line Research Articles

TROP2 regulates cisplatin sensitivity of triple-negative breast cancer cells by regulating endoplasmic reticulum stress.

Triple-negative breast cancer (TNBC) is a kind of breast cancer with a high metastasis rate and poor prognosis. As a transmembrane glycoprotein, tumor-associated calcium signal transducer 2 (TROP2) plays a certain role in the cancers. This study aimed to explore the potential mechanism of TROP2 affecting cisplatin (CDDP) resistance in TNBC from endoplasmic reticulum stress (ERS). MDA-MB-231 and CDDP-resistant cell lines MDA-MB-231/CDDP were used in this study, and the expression of TROP2 was detected by western blotting. After transfecting with the interference sequence of siRNA targeting TROP2, cell proliferation and apoptosis were detected by the cell counting kit-8, colony formation, and flow cytometry, and the expression of ERS-marker proteins was detected by western blotting. Furthermore, the effects of ERS in TROP2 on drug resistance of TNBC cells were explored by using ERS inhibitor 4-phenylbutyric acid (4-PBA). Results found that TROP2 expression in MDA-MB-231/CDDP was significantly upregulated compared with MDA-MB-231. The expression of TROP2 in MDA-MB-231/CDDP was significantly decreased after transfection with siRNA-TROP2, and the proliferation of MDA-MB-231 and MDA-MB-231/CDDP cells was significantly decreased after further induction with CDDP. TROP2 significantly affected TNBC cell cloning, apoptosis, and the expression of ERS-related marker proteins, while 4-PBA reversed the promoting effects of siRNA-TROP2 on apoptosis and ERS, as well as the inhibitory effects on cell proliferation, suggesting that TROP2 affected the resistance of TNBC cells to CDDP through ERS. In conclusion, TROP2 inhibited apoptosis of TNBC cells, improved the cell cloning ability, and regulated the sensitivity of TNBC cells to CDDP through ERS.

Circ-ILF2 in oral squamous cell carcinoma promotes cisplatin resistance and induces M2 polarization of macrophages.

Cisplatin (CDDP) chemoresistance is one of the predominant factors in oral squamous cell carcinoma (OSCC) treatment failure. Uncovering the mechanisms underlying CDDP resistance is of great importance in OSCC therapy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs, which are reported to participate in the progression of various diseases, including cancer. However, the function of circRNAs in CDDP resistance in OSCC remains unclear. Quantitative reverse transcription PCR was used to search for different circRNAs between OSCC cell lines and CDDP-resistant cell lines. The results showed that circ-ILF2 expression was higher in CDDP-resistant OSCC cell lines. The stability of circ-ILF2 was also confirmed using RNase R and actinomycin D assays. Functional experiments, including cytotoxicity, apoptosis and growth rate assays, showed that upregulation of circ-ILF2 contributes to CDDP resistance. Luciferase reporter-gene, RNA pull-down and quantitative real-time PCR (RT-qPCR) assays showed that circ-ILF2 functions as a microRNA sponge for miR-1252. Luciferase reporter assays, RNA pull-down, RT-qPCR and Western blotting showed that miR-1252 directly targeted and regulated the expression of KLF8. Circ-ILF2 plays an important role in CDDP resistance in OSCC. Circ-ILF2 exerts its function through the miR-1252/KLF8 pathway. In addition, tumour-associated macrophages (TAM) play important roles in cancer progressions, our results showed that circ-ILF2 in OSCC cells induced the M2 polarization of macrophages which provided new thoughts on immunotherapy. Our results suggest that circ-ILF2 may represent a potential therapeutic target in CDDP-resistant OSCC.

Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma.

Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients.

MFAP2 enhances cisplatin resistance in gastric cancer cells by regulating autophagy.

Cisplatin (CDDP) is of importance in cancer treatment and widely used in advanced gastric cancer (GC). However, its clinical usage is limited due to its resistance, and the regulatory mechanism of CDDP resistance in GC has not yet been fully elucidated. In this study, we first conducted a comprehensive study to investigate the role of MFAP2 through bioinformatics analysis. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were applied to downloadgene expression data and clinicopathologic data, and the differentially expressed genes (DEGs) were further analyzed. Then, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and survival analysis were conducted. Furthermore, according to the clinicopathological characteristics of TCGA, clinical correlation analysis was conducted, and a receiver operating characteristic curve (ROC) was plotted. We revealed that FAP, INHBA and MFAP2 were good diagnostic factors of GC. However, the mechanism of MFAP2 in GC remains elusive, especially in the aspect of chemotherapy resistance. We developed the CDDP-resistant cell line, and found that MFAP2 was upregulated in CDDP-resistant cells, and MFAP2-knockdown improved CDDP sensitivity. Finally, we found that MFAP2 enhanced CDDP resistance by inducing autophagy in drug-resistant cell lines. The above results suggested that MFAP2 could affect the chemotherapy resistance by altering the level of autophagy in GC patients as a potential therapeutic target.

Potential New Therapeutic Approaches for Cisplatin-Resistant Testicular Germ Cell Tumors.

Testicular germ cell tumors (TGCTs), a group of heterogeneous neoplasms, are the most frequent tumors of teenagers and young men, with the incidence rising worldwide. High cure rates can be achieved through cisplatin (CDDP)-based treatment, but approximately 10% of patients present refractory disease and virtually no treatment alternatives. Here, we explored new strategies to treat CDDP-resistant. In vitro TGCT CDDP-resistance model was established and differential mRNA expression profiles were evaluated using NanoString technology. Then, TGCT cell lines were treated with four potential drugs (PCNA-I1, ML323, T2AA, and MG-132) to overcome CDDP-resistance. We found several differentially expressed genes related to DNA repair and cell cycle regulation on CDDP-resistant cell line (NTERA-2R) compared to parental cell line (NTERA-2P), and the proteasome inhibitor MG-132 demonstrated cytotoxic activity in all cell lines evaluated, even at a nanomolar range. MG-132 also enhanced cell lines' sensitivity to CDDP, increasing apoptosis in both NTERA-2P and NTERA-2R. MG-132 emerges as a potential new drug to treat CDDP-resistant TGCT. Targeted therapy based on molecular mechanism insights may contribute to overcome acquired chemotherapy CDDP-resistance.

JMJD2C mediates the MDM2/p53/IL5RA axis to promote CDDP resistance in uveal melanoma

Chemotherapy resistance poses an obstacle for effective treatment of uveal melanoma. In this study, we aim to investigate the effects of jumonji domain containing 2C (JMJD2C)-mediated mouse double minute-2 homolog (MDM2)/p53/interleukin 5 receptor subunit alpha (IL5RA) axis on cisplatin (CDDP) resistance in uveal melanoma. RT-qPCR and Western blot assay were performed to determine their expression patterns in uveal melanoma cell line (MUM-2B) and CDDP-resistant cell line (MUM-2B/CDDP). The enrichment of H3K9me3 in MDM2 promoter region was examined by ChIP, and the binding between p53 and ubiquitin in MUM-2B cells testified by co-IP assay. Following overexpression or silencing of JMJD2C/MDM2/p53/IL5RA, the 50% concentration of inhibition (IC50) and the biological characteristics of MUM-2B and MUM-2B/CDDP cells were examined using CCK-8 assay, SA-β-gal staining, fluorescence-activated cell sorting analysis, and Transwell assay. Finally, the tumorigenicity of transplanted MUM-2B and MUM-2B/CDDP cells in nude mice was assessed. JMJD2C was documented to be highly expressed in uveal melanoma cells, promoting the CDDP resistance. Histone demethylase JMJD2C removed the H3K9me3 modification of MDM2 promoter, which promoted the expression of MDM2. MDM2 enhanced the IL5RA expression through stimulating the ubiquitination and degradation of p53, thus inducing CDDP resistance of uveal melanoma cells. Furthermore, the results of in vivo experiments revealed that JMJD2C mediated the MDM2/p53/IL5RA axis to expedite the growth of uveal melanoma and augment the CDDP resistance. Taken together, JMJD2C can induce histone demethylation to upregulate MDM2, thereby ubiquitinating p53 and upregulating IL5RA. As a consequence, CDDP resistance in uveal melanoma is ultimately accelerated.

Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy

Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples resistant to platinum-based treatments. Genetic BNIP3 silencing or pharmacological inhibition of autophagosome formation re-sensitizes these cells to CDDP. Our study identifies inhibition of BNIP3-driven mitophagy as a potential therapeutic strategy to counteract CDDP resistance in ovarian carcinoma and osteosarcoma.

Increased PD-L1 Expression in Acquired Cisplatin-Resistant Lung Cancer Cells via Mir-181a.

Cancer immunotherapy has dramatically improved the prognosis of non-small cell lung cancer (NSCLC). In tumor cells, programmed death ligand-1 (PD-L1), also known as cluster of differentiation 274 (CD274), is a key target for cancer immunotherapy. Cisplatin (CDDP), a first-class NSCLC treatment drug, reportedly induces PD-L1 expression, and regulates cancer immunity. Herein, the regulatory mechanism of PD-L1 was investigated in CDDP-treated NSCLC and acquired CDDP-resistant NSCLC. Two types of NSCLC cell lines, A549 and H69, and their CDDP-resistant cell lines, A549R and H68R, were used to investigate PD-L1 expression and microRNA mir-181a expression. Murine lung cancer LL/2 cells were injected to mice for in vivo study. Although CDDP induced PD-L1 expression in A549 and H69 cells, A549R and H69R cells expressed extremely higher levels of PD-L1. CDDP-induced mir-181a was detected in A549 and H69 cells, but not A549R and H69R cells. Moreover, the CDDP-induced ATM-mir-181a-c-FOS pathway repressed PD-L1 expression in A549 cells, while A549R cells blocked this negative regulatory mechanism to further increase PD-L1 expression. Exogenous mir-181a in LL/2 cells could repress the intratumoral exhausted T cells, and increase the T cells function, and repress the tumor growth. Increased PD-L1 expression in acquired cisplatin-resistant lung cancer cells is dependent on mir-181a in NSCLC.

Ginkgolide B Regulates CDDP Chemoresistance in Oral Cancer via the Platelet-Activating Factor Receptor Pathway.

The platelet-activating factor receptor (PAFR) is a key molecule that participates in intracellular signaling pathways, including regulating the activation of kinases. It is involved in cancer progression, but the detailed mechanism of its chemosensitivity is unknown. The purpose of the current study was to elucidate the mechanism regulating cisplatin (CDDP) sensitivity through PAFR functions in oral squamous cell carcinoma (OSCC). We first analyzed the correlation between PAFR expression and CDDP sensitivity in seven OSCC-derived cell lines based upon cell viability assays. Among them, we isolated 2 CDDP-resistant cell lines (Ca9-22 and Ho-1-N-1). In addition to conducting PAFR-knockdown (siPAFR) experiments, we found that ginkgolide B (GB), a specific inhibitor of PAFR, enhanced both CDDP chemosusceptibility and apoptosis. We next evaluated the downstream signaling pathway of PAFR in siPAFR-treated cells and GB-treated cells after CDDP treatment. In both cases, we observed decreased phosphorylation of ERK and Akt and increased expression of cleaved caspase-3. These results suggest that PAFR is a therapeutic target for modulating CDDP sensitivity in OSCC cells. Thus, GB may be a novel drug that could enhance combination chemotherapy with CDDP for OSCC patients.

Anticancer effects of non-steroidal anti-inflammatory drugs against cancer cells and cancer stem cells

Certain non-steroidal anti-inflammatory drugs (NSAIDs) are known to have anticancer effects. However, it is unclear whether all NSAIDs have anticancer effects, and thus far, very few studies have compared the antitumor effects among multiple NSAIDs. Therefore, we aimed to identify NSAIDs that enhance the anticancer effect of cisplatin (CDDP); the effects of 17 NSAIDs in lung cancer cells and their spheroids as cancer stem cells (CSCs) were evaluated. Some of the NSAIDs showed cytotoxic effects against A549 and SBC-3 cells and their CDDP-resistant cell lines (A549/DDP and SBC-3/DDP cells, respectively). In addition, co-addition of CDDP and celecoxib, which showed cytotoxic effects, increased the resistance to CDDP by increasing SLC7A11, which is one of the CDDP resistance mechanisms, in A549/DDP and SBC-3/DDP cells. On the other hand, celecoxib also showed antitumor effects on the spheroids of A549/DDP and SBC-3/DDP cells, and enhanced the antitumor effect of CDDP while increasing the mRNA levels of SLC7A11. Moreover, diclofenac was also cytotoxic and enhanced the cytotoxic effect of CDDP in cancer cells and CSCs. In conclusion, some NSAIDs including celecoxib and diclofenac may enhance the therapeutic efficacy of CDDP.

Association of ALDH1A1-NEK-2 axis in cisplatin resistance in ovarian cancer cells

Development of acquired resistance to cisplatin (CDDP) is a major obstacle in the treatment of ovarian cancer patients. According to the cancer stem cell (CSC) hypothesis, the recurrence and chemoresistance are presumed to be linked to cancer stem/progenitor cells. Here, we investigated the CSC-like phenotypes and mechanism of chemoresistance in CDDP resistant ovarian cancer cells. A well-established CDDP sensitive ovarian cancer cell line A2780 and its resistant population A2780-Cp were used. We also developed a supra resistant population (SKOV3-Cp) from a naturally CDDP resistant cell line SKOV3. Both resistant/supra resistant cell lines showed significantly higher self-renewal capability than their parental counterparts. They also showed significant resistance to apoptosis and sub-G1 arrest by CDDP treatment. Stem cell marker ALDH1 positivity rates were higher both in A2780-Cp and SKOV3-Cp cell lines than in their counterparts, quantified by Aldefluor assay kit. Hoechst 33342 dye effluxing side populations were increased up to about five folds in A2780-Cp cells and two folds in SKOV3-Cp cells compared to A2780 and SKOV3 cells, respectively. Among major stemness related genes (POU5F1/OCT4, SOX2, NANOG, NES, BMI1, KLF4 and ALDH1A1), ALDH1A1 and KLF4 were significantly overexpressed in both resistant/supra resistant cells. Silencing ALDH1A1 in A2780 and A2780-Cp cells using siRNA greatly reduced the stem cell population and sensitized cells to CDDP. Moreover, silencing of ALDH1A1 reduced the transcript and protein level of its downstream target NEK-2. We also observed the downregulation of ABC transporters (ABCB1/MDR1, ABCG2 and ABCC1/MRP1) either by ALDH1A1 or NEK-2 silencing and upreguation of ABCB1/MDR1 due to the overexpression of NEK-2. Taken together, the present study suggests that stemness gene ALDH1A1 can be involved in CDDP resistance through the upregulation of NEK-2 in ovarian cancer.

MiR-194 Inhibits Ovarian Cancer Cell Proliferation and Reduces Cisplatin Resistance by Targeting Yes-Associated Protein

Elevated expression of Yes-associated protein (YAP1) is associated with ovarian cancer. Bioinformatics analysis showed a relationship between miR-194 and YAP1. Our study intends to assess whether miR-194 regulates YAP1 expression and affects the proliferation of ovarian cancer cells and CDDP resistance. CDDP-resistant cell line A2780/CDDP was established and the expression of miR-194 and YAP1 in parental A2780 cells and normal ovarian epithelial IOSE80 cells were compared. A2780/CDDP cells were separated into miR-NC group and miR-194 mimic group followed by analysis of miR-194 and YAP1 expression, and cell apoptosis and proliferation by flow cytometry. There was a targeted relationship between miR-194 and YAP1 mRNA. A2780/CDDP cells had the lowest miR-194 expression followed by A2780 cells and IOSE80 cells. In addition, YAP1 level was highest in A2780/CDDP cells followed by A2780 cells and IOSE80 cells. Compared with miR-NC group, miR-194 expression was significantly increased in miR-194 mimic transfection group and YAP1 protein expression was significantly decreased, with increased cell apoptosis and reduced cell proliferation ability. Decreased miR-194 expression and increased YAP1 expression are related to ovarian cancer CDDP resistance. Increased miR-194 can down-regulate YAP1, inhibit ovarian cancer cell proliferation, promote cell apoptosis, and reduce CDDP resistance.

MiR-205 Promotes Apoptosis of Cervical Cancer Cells and Enhances Drug Sensitivity of Cisplatin by Inhibiting YAP1.

Objective: Elevated expression of Yes-associated protein (YAP1) involves in the pathogenesis of cervical cancer. Bioinformatics analysis showed a targeting relationship between miR-205 and the 3'-UTR of YAP1. In this study, we aim to explore the role of miR-205 in the proliferation, apoptosis, or cisplatin (CDDP) resistance of cervical cancer cells. Patients and Methods: The dual luciferase reporter gene assay verified the relationship between miR-205 and YAP1. The CDDP-resistant cell line Hela/CDDP cells were cultured in vitro and divided into miR-NC group, miR-205 mimic group, and miR-205 inhibitor group followed by analysis of the expression of miR-205 and YAP1 mRNA by quantitative real-time polymerase chain reaction (qRT-PCR), and YAP1 protein level by western blot. Results: There was a targeted relationship between miR-205 and YAP1 mRNA. Compared with cervical cell line HCerEpiC cells, miR-205 expression was significantly decreased and YAP1 mRNA and protein expression was significantly increased in Hela cells (p < 0.01). Compared with miR-NC group, YAP1 protein expression in HeLa/CDDP cells was significantly decreased, cell apoptosis was increased, and proliferation was inhibited in miR-205 mimic-transfected Hela/CDDP cells (p < 0.01). Opposite results were obtained in miR-205 inhibitor-transfected Hela/CDDP cells. Conclusions: The expression of miR-205 is related to the CDDP resistance of cervical cancer cells. Increasing the expression of miR-205 can downregulate the expression of YAP1, inhibit the proliferation and promote apoptosis of cervical cancer cells, and enhance the sensitivity to CDDP.

Synergistic enhancement of efficacy of platinum drugs with verteporfin in ovarian cancer cells

BackgroundEpithelial ovarian cancers (EOCs) comprises the majority of malignant ovarian neoplasms. Combination treatment with chemotherapeutic agents seems to be a promising strategy in ovarian cancer (OVCA) patients in order to overcome drug resistance. In this in vitro study, we investigated the therapeutic efficacy of verteporfin (VP) alone and in combination with cisplatin (CDDP), carboplatin (CP) and paclitaxel (Taxol). The main objectives of this study are to determine the nature of interactions between VP and CDDP/CP/Taxol and to understand the mechanism of action of VP in OVCA cells.MethodsThe efficacy of VP on cell proliferation, cytotoxicity, invasion and clonogenic capacity was assayed in CDDP-sensitive (COV504, OV-90) and CDDP-resistant (A2780Cis) cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using MTT assay and Cell Viability Blue assay. The effects of drugs on the metabolic functions were studied using matrigel invasion assay and clonogenic assay. Immunoblot analysis was carried out to investigate changes in YAP and cell cycle genes. Changes in the cytokines due to drug treatments were analyzed using a cytokine array.ResultsTreatment with VP inhibited cell proliferation, invasion and increased cytotoxicity of OVCA cells. We observed that VP chemosensitized CDDP-resistant cells, even at lower doses. When added either in constant or non-constant ratios, VP produced synergistic effects in combination with CDDP/CP/Taxol. A cytokine array identified upregulation of cytokines in OVCA cells that were inhibited by VP treatment.ConclusionsEither in cisplatin-resistant cell lines or cisplatin-sensitive cell lines, VP proves to be more efficient in inhibiting cell proliferation and inducing cytotoxicity. Our results suggest that novel combinations of VP with CDDP or CP or Taxol might be an attractive therapeutic strategy to enhance OVCA chemosensitivity. The fact that lower doses of VP are effective in chemosensitizing the CDDP-resistant cells, might ultimately lead to the development of an innovative combination therapy for the treatment of OVCA patients.

MiR-194 Regulates Cisplatin Resistance in Colorectal Cancer Cells Through Targeting Yes-Associated Protein

Elevated Yes-associated protein (YAP1) expression is associated with colorectal cancer. Bioinfor-matics analysis showed a targeting relationship between miR-194 and YAP13′-UTR. Our study assessed miR-194’s role in proliferation, apoptosis, and CDDP resistance of colorectal cancer cells. The CDDP-resistant cell line SW480/CDDP was established and miR-194 and YAP1 level in parental SW480 cells and normal intestinal epithelial HCoEpiC cells was measured. SW480/CDDP cells were separated into control group, miR-NC group and miR-194 mimic group followed by analysis of miR-194 and YAP1 level, cell apoptosis and proliferation by flow cytometry. There was a targeted regulatory relationship between miR-194 and YAP1 mRNA. miR-194 was significantly upregulated in SW480/CDDP cells compared to SW480 cells and downregulated in SW480 cells compared to HCoEpiC cells. Whereas, opposite YAP1 expression profiles were found in SW480/CDDP, SW480 and HCoEpiC cells. miR-194 mimic significantly upregulated miR-194 in the SW480/CDDP cells, with decreased YAP1 expression, increased cell apoptosis, decreased cell proliferation and reduced IC50. Decreased miR-194 and increased YAP1 expression involve in CDDP resistance of colorectal cancer. Increase of miR-194 expression can inhibit colorectal cancer cell proliferation, promote apoptosis and reduce CDDP resistance by down-regulating YAP1 expression.

MiR-203 Regulates DJ-1/Phosphatase and Tensin Homologue Deleted on Chromosome Ten/Phosphatidylinositol-3 Kinase/Protein Kinase B Pathway and Affects Proliferation, Apoptosis and Cisplatin Resistance of Ovarian Cancer Cells

DJ-1 negatively regulates PTEN and plays a role in tumorigenesis and progression. Abnormal miR-203 expression is associated with ovarian cancer. miR-203 was predicted to have a relationship with DJ-1 3-UTR. Our study assessed miR-203’s role in ovarian cancer cell cisplatin (CDDP) resistance. The CDDP-resistant cell line SKOV3/CDDP was established and compared with the expression of miR-203 and DJ-1 in the parental SKOV3 cells. SKOV3/CDDP cells were separated into miR-NC group and miR-203 mimic group followed by analysis of DJ-1, PTEN and p-AKT expression, cell apoptosis and proliferation. There was a targeted relationship between miR-203 and DJ-1 mRNA. miR-203 and PTEN protein expression in SKOV3/CDDP cells was significantly reduced compared to SKOV3 cells with significantly upregulated DJ-1. miR-203 mimic significantly upregulated miR-203, decreased DJ-1 and p-AKT protein expression and elevated PTEN expression along with increased cell apoptosis and reduced cell proliferative ability. Decreased miR-203 expression and increased DJ-1 expression participate in drug resistance in ovarian cancer cells. miR-203 inhibits DJ-1 expression, affects PTEN-PI3K/AKT signaling, inhibits ovarian cancer cell proliferation and promotes apoptosis, and reduces CDDP resistance.

MiR-132 inhibits migration and invasion and increases chemosensitivity of cisplatin-resistant oral squamous cell carcinoma cells via targeting TGF-β1

ABSTRACT Numerous findings have demonstrated that MicroRNAs dysregulation plays a key role in many neoplasms, including oral squamous cell carcinoma (OSCC), yet the potential mechanisms of microRNAs in chemo-resistance remain elusive. Here, we analyzed the miR-132 expression in OSCC tissues and OSCC cell lines, and explored it role and mechanisms on invasion and migration and cisplatin (CDDP)-induced cell death. The clinical tissues of 37 patients with OSCCs and paired normal tissues were collected. The miR-132 expression in OSCC tissues and cell lines were detected by reverse transcription-quantitative polymerase chain reation (RT-qPCR). The in vitro repopulation models were established to mimic the biological processes of OSCC. The results showed that miR-132 expression was significantly decreased in the OSCC tissues and CDDP resistant OSCC cell line (CAL-27/CDDP). miR-132 mimic inhibited cell proliferation, invasion, migration and enhanced the pro-apoptotic ability of CDDP. On the contrary, downregulation of miR-132 promoted proliferation, invasion, migration and conferred OSCC cell resistance to CDDP-induced apoptosis in vitro. The TGF-β1 expression in OSCC tissues and CAL-27/CDDP cells was significantly higher. miR-132 significantly inhibited the TGF-β1/Smad2/3 signals. TGF-β1 upregulation significantly promoted OSCC cell proliferation and resumed OSCC cell chemo-resistance in the miR-132 overexpressing cells, which is contrary to the function of miR-132. In summary, miR-132 acts as a tumor suppressor and exerts a substantial role in inhibiting the proliferation, invasion, and enhanced the chemosensitivity to CDDP of OSCC via regulating TGF-β1/Smad2/3 signals in vitro. These observations indicate that miR-132 may be a suitable therapeutic target for the treatment of OSCC.

Circular RNA CDR1-AS contributes to pemetrexed and cisplatin chemoresistance through EGFR/PI3K signaling pathway in lung adenocarcinoma

Recent studies found circRNAs were involved in tumorigenesis and became new tumor biomarkers and therapeutic targets in lung adenocarcinoma (LUAD), which played a critical role in various biological processes and had been implicated in resistance to chemotherapeutic drugs. However, the role of CDR1-AS in chemoresistance of LUAD to pemetrexed (PTX) and cisplatin (CDDP) is poorly understood. Here, we found that CDR1-AS was up-regulated in LUAD tissues and cell lines, its high-expression was relevant to smoking history, T stage and neoadjuvant chemotherapy (PTX and CDDP) of LUAD patients. CDR1-AS was an independent prognostic biomarker for LUAD patients. CDR1-AS was highly expressed in PTX and CDDP resistant LUAD tissues and cell line (A549/CR). Silence of CDR1-AS re-sensitized A549/CR cells to PTX and CDDP. CDR1-AS was closely related with EGFR/PI3K signaling pathway in A549/CR cells. The activating of EGFR/PI3K pathway mostly restored the effecting of CDR1-AS silence on PTX and CDDP sensitivity in A549/CR cells, CDR1-AS contributed to PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD. In conclusion, the CDR1-AS is high-expressed in LUAD and is an independent prognostic biomarker for LUAD patients. The high-expression of CDR1-AS is related with the PTX and CDDP insensitivity of LUAD patients, CDR1-AS promotes PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD.

MiR-203 Affects Proliferation, Apoptosis and Cisplatin Resistance of Gastric Cancer Cells Through DJ-1-PTEN-PI3K/AKT Pathway

DJ-1 negatively regulates phosphatase and tensin homolog gene (PTEN). Abnormal miR-203 expression is associated with gastric cancer. Bioinformatics analysis showed a targeting relationship between miR-203 and DJ-1 3′-UTR. Our study evaluated the role of miR-203 gastric cancer cell proliferation, apoptosis, and cisplatin (DDP) resistance. The CDDP-resistant cell line SGC7901/CDDP was established and divided into miR-NC group and miR-203 mimic group followed by detecting DJ-1, PTEN and p-AKT expression, and cell apoptosis and proliferation by flow cytometry. There was a targeted relationship between miR-203 and DJ-1 mRNA. miR-203 expression in SGC7901/CDDP cells was significantly reduced compared with SGC7901 cells with elevated DJ-1 mRNA and protein level. Compared with miR-NC group, DJ-1 and p-AKT in SGC7901/CDDP cells was significantly downregulated in miR-203 mimic transfection group, while PTEN expression was significantly increased, cell apoptosis was increased, and proliferation and CDDP resistance were reduced. Decreased miR-203 and increased DJ-1 level is associated with gastric cancer drug resistance. Elevated miR-203 can downregulate DJ-1, affect the activity of PTEN-PI3K/AKT pathway, inhibit gastric cancer cell proliferation, promote cell apoptosis, and enhance the drug sensitivity to CDDP.

MiR-129 reduces CDDP resistance in gastric cancer cells by inhibiting MAPK3.

Abnormal expression of mitogen-activated protein kinase 3 (MAPK3) is related to invasion, metastasis, and drug resistance of multiple tumor cells. MiR-129 expression is associated with gastric cancer. Bioinformatics analysis showed a targeting relation between miR-129 and MAPK3. This study investigated whether miR-129 plays a role in regulating MAPK3 expression, affecting proliferation, apoptosis, and cisplatin (CDDP) resistance of gastric cancer cells. The dual-luciferase reporter gene assay was used to assess the targeted regulation between miR-129 and MAPK3. The expression of miR-129 and MAPK3 in CDDP-resistant cell line MGC-803/CDDP and the parental MGC-803 cells was measured. MGC-803/CDDP cells were cultured in vitro and divided into miR-NC group and miR-129 mimic group. The expression of MAPK3 and p-MAPK3 protein were detected by Western blot and the effect of CDDP treatment on cell apoptosis and proliferation was detected by flow cytometry. There was a targeted regulation relation between miR-129 and MAPK3 mRNA. MiR-129 expression in MGC-803/CDDP cells was significantly lower than that in MGC-803 cells and the expression of MAPK3 mRNA and protein was significantly higher than that in MGC-803 cells. Compared with miR-NC group, the expression of MAPK3 and p-MAPK3 in MHC-803/CDDP cells in miR-129 mimic transfection group was significantly decreased, with increased cell apoptosis and reduced cell proliferation. The decreased expression of miR-129 and the up-regulation of MAPK3 are associated with CDDP resistance in gastric cancer cells. Overexpression of miR-129 inhibits MAPK3 expression and cell proliferation, it induces cell apoptosis and reduces CDDP resistance.