TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway

Ghoshal-Gupta, Sampa; Kutiyanawalla, Ammar; Lee, Byung Rho; Ojha, Juhi; Nurani, Aliya; Mondal, Ashis; Kolhe, Ravindra; Rojiani, Amyn M.; Rojiani, Mumtaz V.

doi:10.18632/oncotarget.23832

Cited by 18 publications

(15 citation statements)

References 55 publications

(53 reference statements)

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“…Several recent studies have documented a potential chemoresistant function of TIMP-1 [8,9]. Our own studies have confirmed that the high expression of TIMP-1 results in activation of pro-survival and anti-apoptotic signaling through the extracellular-signal-regulated kinase (ERK) and BCL2 associated agonist of cell death (BAD) pathway, as well as the down-regulation of miR-125a-5p in NSCLCs [9,10]. Although the understanding of this function of TIMP-1 is starting to gain grounds, the precise mechanisms by which TIMP-1 causes chemoresistance remains elusive.…”

Section: Introductionmentioning

confidence: 63%

“…To address the effect of TIMP-1 in chemotherapy, NSCLC A549 and H460 and their TIMP-1 non-target (NT) and knock-down (KD) clones were employed (Supplementary Figure S1A). The knockdown of the TIMP-1 gene does not affect the proliferation rate in both NSCLC cell lines [10]. These cells were analyzed for apoptosis after treatment with Gemcitabine or Cisplatin, which are routinely used as frontline chemotherapeutic agents for lung carcinomas.…”

Section: Resultsmentioning

confidence: 99%

“…Human NSCLC cell lines (A549 and H460) were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA). A549- and H460-derived cell clones, encoding non-target scrambled shRNA (-NT) or TIMP-1-specific knockdown shRNA (-KD) sequences, characterized in our previous studies [10] were used. A549 and its clones were cultured in F-12K medium, and H460 and its clones were grown in RPMI Medium 1640 (Sigma-Aldrich, St. Louis, MO, USA) as per ATCC recommendations.…”

Section: Methodsmentioning

confidence: 99%

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TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC

Xiao

Wang

Howard

et al. 2019

Cancers

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Elevated tissue inhibitor of metalloproteinase-1 (TIMP-1) is a negative prognosticator in non-small cell lung carcinoma NSCLC patients. This study sought to identify mechanisms whereby TIMP-1 impacts anticancer therapy. Using NSCLC cells and their TIMP-1 knockdown clones, we examined the chemoresistance against two chemotherapeutic agents, Gemcitabine and Cisplatin, as identified by increased apoptosis in the knockdown clones. A bead-based cytokine screening assay identified interleukin-6 (IL-6) as a key factor in chemoresistance. Exogenous human recombinant rhTIMP-1 or rhIL-6 resulted in reduced apoptosis. IL-6 expression was closely correlated with TIMP-1 kinetics and was upregulated by the addition of exogenous TIMP-1 while TIMP-1 neutralizing antibodies delayed IL-6 elevation. IL-6 production was regulated by TIMP-1, exerting its effect via activation of downstream signal transducer and activator of transcription 3 (STAT3) signaling. Both molecules and their documented transcription factors were upregulated and activated in chemoresistant NSCLC cells, confirming the roles of TIMP-1 and IL-6 in chemoresistance. To examine the role of these genes in patients, survival data from lung adenocarcinoma (LUAD) patients was curated from the cancer genome atlas (TCGA) database. Kaplan-Meier analysis found that individuals expressing low TIMP-1 and IL-6 have a higher survival rate and that the two-gene signature was more significant than the single-gene status. We define for the first time, a regulatory relationship between TIMP-1 and IL-6 in NSCLCs, suggesting that the TIMP-1/IL6 axis may be a valuable prognostic biomarker. Therapeutic interventions directed at this dual target may improve overall prognosis while negatively affecting the development of chemoresistance in NSCLC.

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Section: Introductionmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC

Xiao

Wang

Howard

et al. 2019

Cancers

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“…Moreover, the experimental results showed that miR-125a-5p could improve the sensitivity of tumor cells to radiotherapy by upregulating p53 and enhancing apoptosis in lung cancer. Similarly, a previous study found that miR-125a-5p contributes to p53 activation [42]. Following radiation therapy-induced DSB, two repair pathways are activated: homologous recombination and nonhomologous end joining (NHEJ); of these, the most important pathway is NHEJ, which catalyzes the random connection of the two ends of DSBs through DNA-PKCs, Ku70, Ku80, and XRCC4 to repair DNA [39].…”

Section: Discussionmentioning

confidence: 86%

MiR-125 family improves the radiosensitivity of head and neck squamous cell carcinoma

Wang

Liu

Tan

et al. 2022

Preprint

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Background MiRNAs can affect the radiosensitization of head and neck squamous cell carcinoma (HNSCC). We aimed to analyze the function of miR-125 family members in HNSCC using The Cancer Genome Atlas (TCGA) and determine their effect on radiation in laryngeal squamous cell cancer (LSCC). Methods First, we performed survival analysis for patients with laryngeal cancer, conducted pathway enrichment analysis, and predicted target genes. Then, we performed transfection, cell proliferation assays, reverse transcription polymerase chain reaction, apoptosis assays, micronucleus tests, and western blotting on hep-2 cells selected with puromycin. Results MiR-125 family members exhibited significantly different expression in HNSCC. MiR-125b-1-3p, miR-125b-2-5p, and miR-125b-5p expression was significantly associated with tumor–node–metastasis staging, clinical cancer stages, and early histological grades in HNSCC. Radiation therapy had a statistically significant effect on the expression of all miR-125 family members, except miR-125a-3p. Moreover, miR-125a-5p was related to overall survival in LSCC. Thus, we predicted 110 target genes and seven hub genes of miR-125a-5p. MiR-125a-5p expression was significantly improved after transfection, and the proliferation rate of cells transfected with lentivirus vector expressing miR-125a-5p was significantly reduced compared to that of parental and negative control group cells. The radiation effect was also enhanced in cells transfected with miR-125a-5p. The ratio of apoptotic cells transfected and exposed to X-rays (10 Gy) was distinctly higher than that of the Ad-control group. Micronucleus assay results in the Ad-miR-125a-5p group were significantly different from those in the parental and Ad-control groups. Western blotting analysis revealed that miR-125a-5p upregulated the apoptotic regulators P53 and rH2AX. Thus, miR-125a-5p may increase radiosensitivity in LSCC via upregulation of pro-apoptotic genes. Conclusions MiR-125 family members could be prognostic biomarkers of HNSCC, and miR-125a-5p may substantially improve HNSCC sensitivity to radiotherapy by activating P53. Upregulating miR-125a-5p via lentivirus vectors may be a novel strategy to strengthen the effect of radiotherapy on laryngeal cancer.

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“…We screened and validated BCL2 as the downstream target of miR-181a-5p. Ghoshal-Gupta et al [47] and Srilatha et al [48] revealed an interaction between BCL2 and TIMP1. Srilatha et al [48] verified that BCL2 can interact with TIMP1 using a co-immunoprecipitation (co-IP) experiment.…”

Section: Discussionmentioning

confidence: 98%

Screening and identification of miR-181a-5p in oral squamous cell carcinoma and functional verification in vivo and in vitro

Yang

et al. 2023

BMC Cancer

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Background Oral squamous cell carcinoma (OSCC) is a common malignant tumor associated with poor prognosis. MicroRNAs (miRNAs) play crucial regulatory roles in the cancer development. However, the role of miRNAs in OSCC development and progression is not well understood. Methods We sought to establish a dynamic Chinese hamster OSCC animal model, construct miRNA differential expression profiles of its occurrence and development, predict its targets, and perform functional analysis and validation in vitro. Results Using expression and functional analyses, the key candidate miRNA (miR-181a-5p) was selected for further functional research, and the expression of miR-181a-5p in OSCC tissues and cell lines was detected. Subsequently, transfection technology and a nude mouse tumorigenic model were used to explore potential molecular mechanisms. miR-181a-5p was significantly downregulated in human OSCC specimens and cell lines, and decreased miR-181a-5p expression was observed in multiple stages of the Chinese hamster OSCC animal model. Moreover, upregulated miR-181a-5p significantly inhibited OSCC cell proliferation, colony formation, invasion, and migration; blocked the cell cycle; and promoted apoptosis. BCL2 was identified as a target of miR-181a-5p. BCL2 may interact with apoptosis- (BAX), invasion- and migration- (TIMP1, MMP2, and MMP9), and cell cycle-related genes (KI67, E2F1, CYCLIND1, and CDK6) to further regulate biological behavior. Tumor xenograft analysis indicated that tumor growth was significantly inhibited in the high miR-181a-5p expression group. Conclusion Our findings indicate that miR-181a-5p can be used as a potential biomarker and provide a novel animal model for mechanistic research on oral cancer.

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TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway

Cited by 18 publications

References 55 publications

TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC

TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC

MiR-125 family improves the radiosensitivity of head and neck squamous cell carcinoma

Screening and identification of miR-181a-5p in oral squamous cell carcinoma and functional verification in vivo and in vitro

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