DNA Repair Genes ERCC1 and BRCA1 Expression in Non-Small Cell Lung Cancer Chemotherapy Drug Resistance

Wang, Shuai; Feng, Li; Zhu, Jianming; Chen, Peng; Liu, Hongxing; Liu, Qi; Han, Jianyong

doi:10.12659/msm.896606

Cited by 28 publications

(18 citation statements)

References 22 publications

(24 reference statements)

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“…Various studies indicate that BCL2associated athanogene-1 (BAG-1) (30,34,35) may promote sensitivity to chemotherapy in NSCLC patients. DNA damage and DNA repair-associated genes and factors have been identified as being involved in DDP resistance (36)(37)(38). Spindle and kinetochore-associated complex subunit 1 (SKA1) is considered to regulate the ERK1/2 and the Akt-mediated signaling pathways in NSCLC cells (39).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of miR-203 increases the sensitivity of NSCLC A549/H460 cell lines to cisplatin by targeting Dickkopf-1

Cheng

Zhang

et al. 2017

Oncology Reports

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The number of new lung cancer cases diagnosed yearly is high, and the mortality rate has not substantially declined. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and adenocarcinoma accounts for the largest proportion of NSCLC. Currently, platinum-based combined chemotherapy, particularly cisplatin (DDP) is still the main form of treatment for advanced NSCLC. However, cisplatin resistance often occurs in patients who receive chemotherapy. Previous studies offer various explanations for how miRNAs affect cisplatin resistance, but the underlying mechanism remains largely unknown. The present study was designed to focus on miR-203 and Dickkopf-1 (DKK1), investigating the potential mechanisms involved in cisplatin resistance in tissues of lung adenocarcinoma and A549/H460 cell lines. In DDP-sensitive NSCLC samples, miR-203 was expressed at a higher level when compared with this level in DDP-insensitive samples, while DKK1 mRNA was expressed at a relatively low level as indicated by qRT-PCR. Dual luciferase reporter assay revealed that DKK1 is a target gene of miR-203 in A549 and H460 cells. Upregulation of miR-203 reduced the IC50 value of cisplatin in the A549 and H460 cells by inhibiting cell growth and promoting cell apoptosis. Similar effects of tumor inhibition and cisplatin sensitization were verified in vivo. Further research showed that both overexpression of miR-203 and knockdown of DKK1 increased the sensitization to DDP with a lower IC50 value. Upon DKK1 knockdown, overexpression of miR-203 had no added effects on the sensitivity of the cells. In addition, miR-203 was unable to sensitize cells with DKK1 that lacked the 3' untranslated region (3'UTR). We conclude that miR-203 targets the 3'UTR of DKK1, and increases cisplatin sensitivity in A549/H460 cell lines.

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Section: Discussionmentioning

confidence: 99%

Overexpression of miR-203 increases the sensitivity of NSCLC A549/H460 cell lines to cisplatin by targeting Dickkopf-1

Cheng

Zhang

et al. 2017

Oncology Reports

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“…At the same time, some people have also studied tolerance to treatment as one of the influencing factors. However, some tumor cells can pass activating self DNA repair mechanisms to resistance to DNA damage drugs [6][7][8] . So some studies have proposed that DNA repair genes have a relationship with the metastasis of breast cancer 9 .…”

Section: -Fluorouracilmentioning

confidence: 99%

The diagnostic value of DNA repair gene in breast cancer metastasis

Yang

Hao

et al. 2020

Sci Rep

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Breast cancer is the most common malignant tumor in China and even in the world. DNA repair genes can lead to tumor metastasis by affecting cancer cell resistance. Studies have preliminarily shown that DNA repair genes are related to breast cancer metastasis, but it is not clear whether they can be used as a prediction of the risk of breast cancer metastasis. Therefore, this study mainly discusses the predictive value of DNA repair genes in postoperative metastasis of breast cancer. The nested case–control method was used in patients with breast cancer metastasis after surgery (n = 103) and patients without metastasis after surgery (n = 103). The proteins and mRNA of DNA repair genes were detected by immunohistochemistry and Real-time PCR respectively. In protein expression, PARP1 (OR 1.147, 95% CI 1.067 ~ 1.233, P < 0.05), XRCC4 (OR 1.088, 95% CI 1.015 ~ 1.166, P < 0.05), XRCC1 (OR 1.114, 95% CI 1.021 ~ 1.215, P < 0.05), ERCC1 (OR 1.068, 95% CI 1.000 ~ 1.141, P < 0.10) were risk factors for postoperative metastasis of breast cancer. In addition, we used the ROC curve to study the optimal critical values of MSH2, MLH1, PARP1, XRCC1, XRCC4, 53BP1, ERCC1 and XPA combined with the Youden index, and the effects of MSH2, MLH1, PARP1, XRCC1, XRCC4, 53BP1, ERCC1 and XPA on breast cancer metastasis were verified again. Among them, the risk of metastasis in the PARP1 high expression group was 3.286 times that of the low expression group (OR 3.286, 95% CI 2.013 ~ 5.364, P < 0.05). The risk of metastasis in the XRCC4 high expression group was 1.779 times that of the low expression group (OR 1.779, 95% CI 1.071 ~ 2.954, P < 0.05). The risk of metastasis in patients with ERCC1 high expression group was 2.012 times that of the low expression group (OR 2.012, 95% CI 1.056 ~ 3.836, P < 0.05). So we can conclude that protein expression of PARP1 (cut-off value = 6, Se = 76.70%, Sp = 79.61%), XRCC4 (cut-off value = 6, Se = 78.64%0, Se = 79.61%), ERCC1 (cut-off value = 3, Se = 89.32%, Sp = 50.49%), suggesting that when the PARP1 score is higher than 6 or the XRCC4 score is higher than 6 or the ERCC1 score is higher than 3, the risk of metastasis will increases. Due to PARP1, XRCC4 and ERCC1 belong to a part of DNA repair gene system, and the three proteins are positively correlated by correlation analysis (rPARP1-XRCC4 = 0.343; rPAPR1-ERCC1 = 0.335; rXRCC4-ERCC1 = 0.388). The combined diagnosis of the PARR1, XRCC4 and ERCC1 have greater predictive value for the risk of metastasis of breast cancer (Se = 94.17%, Sp = 75.73%; OR 11.739, 95% CI 2.858 ~ 40.220, P < 0.05). The postoperative metastasis of breast cancer could be effectively predicted when the immunohistochemical scores met PARP1 (IHC score) > 6, XRCC4 (IHC score) > 6 and ERCC1 (IHC score) > 3. In addition, the combined diagnosis of PARP1, XRCC4 and ERCC1 has great predictive value for the risk of breast cancer metastasis.

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“…Unfortunately, a large proportion of NSCLC patients are diagnosed at an advanced stage with unresectable tumors. For these patients, systemic chemotherapy is an irreplaceable treatment [3,4]. One challenge, however, is that many NSCLC cases exhibit poor response to chemotherapy [5,6].…”

Section: Introductionmentioning

confidence: 99%

miR-202 Enhances the Anti-Tumor Effect of Cisplatin on Non-Small Cell Lung Cancer by Targeting the Ras/MAPK Pathway

Sun¹,

Wei²,

Tian³

et al. 2018

Cell Physiol Biochem

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Background/Aims: KRas is usually mutated in non-small cell lung cancer (NSCLC). The mutated KRas gene is a negative prognostic indicator that promotes tumor proliferation, metastasis, and drug resistance in NSCLC, and thus has become a target for cancer therapy. This study is focused on the effects of the microRNA (miR)-202/KRas axis in regulating chemosensitivity in NSCLC. Methods: Quantitative reverse transcriptase real-time PCR analysis was performed to examine the expression of miR-202. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays were performed to evaluate the sensitivity of cisplatin against NSCLC cells. The miR-202/KRas axis was confirmed by western blot and luciferase reporter assays. Cell apoptosis was measured by flow cytometry. KRas expression, MEK1/2 and ERK1/2 phosphorylation, and activation of caspase-9 and caspase-3 were detected by western blot. Results: A significant decrease in miR-202 expression was observed in NSCLC cells both in vivo and in vitro. In addition, miR-202 expression was associated with drug resistance. Recovery of miR-202 expression levels was found to increase the sensitivity of both NCI-H441 and A549 NSCLC cells to cisplatin treatment. Mechanically, as the Ras/mitogen-activated protein kinase (MAPK) pathway was aberrantly activated in NCI-H441 and A549 NSCLC cells, the overexpression of miR-202 was found to inhibit the Ras/MAPK pathway by targeting the KRas gene. As a result, increased miR-202 expression expanded apoptosis signaling induced by cisplatin in NSCLC cells. Conclusion: The miR-202/KRas axis controlled the chemosensitivity of NSCLC by mediating the Ras/MAPK pathway. Thus, the combination of platinum-based drugs with miR-202 may represent a novel strategy to enhance the anti-tumor effect against NSCLC.

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DNA Repair Genes ERCC1 and BRCA1 Expression in Non-Small Cell Lung Cancer Chemotherapy Drug Resistance

Cited by 28 publications

References 22 publications

Overexpression of miR-203 increases the sensitivity of NSCLC A549/H460 cell lines to cisplatin by targeting Dickkopf-1

Overexpression of miR-203 increases the sensitivity of NSCLC A549/H460 cell lines to cisplatin by targeting Dickkopf-1

The diagnostic value of DNA repair gene in breast cancer metastasis

miR-202 Enhances the Anti-Tumor Effect of Cisplatin on Non-Small Cell Lung Cancer by Targeting the Ras/MAPK Pathway

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