UBE2C Induces Cisplatin Resistance via ZEB1/2-Dependent Upregulation of ABCG2 and ERCC1 in NSCLC Cells

Abstract

Objectives Cisplatin (DDP) is one of the most commonly used chemotherapeutic drugs for several cancers, including non-small-cell lung cancer (NSCLC). However, resistance to DDP eventually develops, limiting its further application. New therapy targets are urgently needed to reverse DDP resistance. Methods The mRNA expression of UBE2C, ZEB1/2, ABCG2, and ERCC1 was analyzed by reverse transcription-polymerase chain reaction. The protein levels of these molecules were analyzed by Western blotting and immunofluorescent staining. Cell proliferation was detected by CCK8 and MTT assays. Cell migration and invasion were analyzed by wound healing assay and Transwell assays. Promoter activities and gene transcription were analyzed by luciferase reporter assay. Results In this study, we examined the effect of UBE2C and ZEB1/2 expression levels in DDP-resistant cells of NSCLC. We confirmed that aberrant expression of UBE2C and ZEB1/2 plays a critical role in repressing the DDP sensitivity to NSCLC cells. Additionally, knockdown of UBE2C significantly sensitized resistant cells to DDP by repressing the expression of ZEB1/2. Mechanistic investigations indicated that UBE2C transcriptionally regulated ZEB1/2 by accelerating promoter activity. This study revealed that ZEB1/2 promotes the epithelial mesenchymal transition and expression of ABCG2 and ERCC1 to participate in UBE2C-mediated NSCLC DDP-resistant cell progression, metastasis, and invasion. Conclusion UBE2C may be a novel therapy target for NSCLC for sensitizing cells to the chemotherapeutic agent DDP.

Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis

“…Still, urine analysis is considered the less invasive procedure for the diagnosis of cancer so far and we here describe some potential new urine biomarkers with good diagnostic values that are also altered in tumor samples. For instance, UBE2C is commonly upregulated in intestinal-type gastric cancer, ovarian cancer, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, HCC, and non-small cell lung cancer [68][69][70][71][72][73][74]. Remarkably, increased UBE2C expression promotes chromosomal instability, cell cycle progression, proliferation and EMT, being positively correlated with worse clinical outcomes, mainly overall survival, lymph node metastasis, and progression-free survival.…”

“…Remarkably, increased UBE2C expression promotes chromosomal instability, cell cycle progression, proliferation and EMT, being positively correlated with worse clinical outcomes, mainly overall survival, lymph node metastasis, and progression-free survival. Of note, experimental inhibition of UBE2C suppressed the malignant phenotypes, surpassing cisplatin resistance in ovarian and non-small cell lung cancers [69,74], in parallel with overcoming sorafenib resistance in HCC [73]. On the other hand, the reports regarding SERPINB1 are still controversial.…”

RETRACTED ARTICLE: Inhibition of ZEB1-AS1 confers cisplatin sensitivity in breast cancer by promoting microRNA-129-5p-dependent ZEB1 downregulation

“…Finally, through the treatment of ZEB1 silence and overexpression in MCF-7 cell line, the role of microRNA-129-5p and ZEB1 in the cisplatin resistance of MCF-7 cells was evaluated. Reports have demonstrated the involvement of ZEB1 with cisplatin resistance in ovarian cancer [43], stomach cancer [44] and non-small cell lung cancer (NSCLC) [45]. Moreover, the downstream genes regulated by ZEB1 include ABCG2 and ERCC1 in NSCLC [46] as well as SLC3A2 in ovarian cancer [43].…”

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

“…EMT is also associated with the expression of ATP-binding cassette (ABC) transporters, membrane proteins responsible for pumping xenobiotics out of the cells (Saxena et al, 2011). Indeed, the correlation between EMT, increased ZEB1/2dependent expression of MDR1 and ABCG2, and resistance to platinum-based drugs was confirmed by the whole transcriptome profiling of ovarian and lung cancer tissues (Zhou Y. et al, 2017;Wu et al, 2019a). Finally, several recent studies demonstrated decreased sensitivity to chemotherapy of primary and metastatic tumor cells in an EMT-dependent manner in both lung and pancreatic cancers (Fischer et al, 2015;Zheng et al, 2015).…”