Abstract
Abstract
Purpose
Long non-coding RNAs (lncRNAs) play vital roles in tumor progression and resistance. Ovarian cancer (OC), a common gynecological cancer, is associated with poor prognosis as it can progress to peritoneal metastasis and develop resistance to chemotherapy. This study aimed to examine the role of lncRNAs in the development of chemotherapy resistance in OC.
Methods
The clinical samples were divided into chemotherapy-sensitive and chemotherapy-resistant groups based on the chemotherapy response at follow-up. The glycolysis levels in the two groups were analyzed using positron emission tomography/computed tomography (PET/CT) scanning and immunohistochemistry. GEO dataset analysis revealed the expression of CTSLP8 in chemotherapy-resistant patients with OC. Two pairs of normal and diamminodichloroplatinum (DDP)-resistant cells were transfected with CTSLP8 overexpression and knockdown constructs to examine the functions of CTSLP8 in the OC cells and elucidate the underlying mechanisms. The in vivo effect of CTSLP8 overexpression and knockdown on the chemotherapy response of tumors was examined using a mouse subcutaneous tumor model. The tissue chips were subjected to fluorescence in situ hybridization and immunohistochemical (IHC) staining to examine the correlation among CTSLP8 expression, DDP resistance, and prognosis in OC.
Results
The dataset analysis demonstrated that CTSLP8 was upregulated in chemotherapy-resistant tumor tissues. CTSLP8 promoted the proliferation and development of DDP resistance in the OC cells. Moreover, CTSLP8 promoted c-Myc expression by facilitating the binding of PKM2 to the promoter region of c-Myc, thereby upregulating glycolysis. The analysis of tissue chips revealed that the upregulation of CTSLP8 was associated with the development of DDP resistance and poor prognosis in patients with OC.
Conclusions
These findings indicate that CTSLP8 forms a complex with PKM2 to regulate c-Myc, and this action results in the upregulation of cellular glycolysis, consequently promoting OC progression and development of chemotherapy resistance.
Headlights
1. CTSLP8 was upregulated in the chemotherapy-resistant tumor tissues.
2. CTSLP8 promoted the proliferation and cisplatin resistance in the OC cells.
3. CTSLP8 promoted glycolysis by facilitating the binding of PKM2 to the promoter region of c-Myc.
4. Inhibition of CTSLP8 or the combination of c-Myc inhibitors with cisplatin were potential therapeutic strategies for chemotherapy-resistant of OC.
Publisher
Springer Science and Business Media LLC
Subject
Health, Toxicology and Mutagenesis,Cell Biology,Toxicology
Reference43 articles.
1. Agarwal R, Kaye SB. “Ovarian cancer: strategies for overcoming resistance to chemotherapy”, Nature reviews. Cancer. 2003;3:502–16.
2. Bouvard C, Lim SM, Ludka J, Yazdani N, Woods AK, Chatterjee AK, Schultz PG, Zhu S. Small molecule selectively suppresses MYC transcription in cancer cells. Proc Natl Acad Sci USA. 2017;114:3497–502.
3. Cheetham SW, Faulkner GJ, Dinger ME. “Overcoming challenges and dogmas to understand the functions of pseudogenes”, Nature reviews. Genetics. 2020;21:191–201.
4. Chen F, Chen J, Yang L, Liu J, Zhang X, Zhang Y, Tu Q, Yin D, Lin D, Wong PP, Huang D, Xing Y, Zhao J, Li M, Liu Q, Su F, Su S, Song E. Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells. Nat Cell Biol. 2019;21:498–510.
5. Chen X, Wan L, Wang W, Xi WJ, Yang AG, Wang T. Re-recognition of pseudogenes: From molecular to clinical applications. Theranostics. 2020;10:1479–99.
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