Long non-coding RNA CTSLP8 mediates ovarian cancer progression and chemotherapy resistance by modulating cellular glycolysis and regulating c-Myc expression through PKM2,Cell Biology and Toxicology

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Long non-coding RNA CTSLP8 mediates ovarian cancer progression and chemotherapy resistance by modulating cellular glycolysis and regulating c-Myc expression through PKM2
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-09-12 , DOI: 10.1007/s10565-021-09650-9
Xiaoduan Li ₁ , Yi Zhang ₂ , Xinjing Wang ₁ , Feikai Lin ₁ , Xi Cheng ₃ , Ziliang Wang ₁ , Xipeng Wang ₁

Affiliation

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.

中文翻译：

长链非编码 RNA CTSLP8 通过调节细胞糖酵解和通过 PKM2 调节 c-Myc 表达来介导卵巢癌进展和化疗耐药

目的

长链非编码 RNA (lncRNA) 在肿瘤进展和耐药中起着至关重要的作用。卵巢癌 (OC) 是一种常见的妇科癌症，预后不良，因为它可以进展为腹膜转移并对化疗产生耐药性。本研究旨在检查 lncRNA 在 OC 化疗耐药性发展中的作用。

方法

根据随访时的化疗反应将临床样本分为化疗敏感组和化疗耐药组。使用正电子发射断层扫描/计算机断层扫描 (PET/CT) 扫描和免疫组织化学分析两组的糖酵解水平。GEO 数据集分析揭示了 CTSLP8 在化疗耐药的 OC 患者中的表达。用 CTSLP8 过表达和敲低构建体转染两对正常细胞和二氨基二氯铂 (DDP) 抗性细胞，以检查 OC 细胞中 CTSLP8 的功能并阐明其潜在机制。使用小鼠皮下肿瘤模型检查了 CTSLP8 过表达和敲低对肿瘤化疗反应的体内影响。

结果

数据集分析表明 CTSLP8 在化疗耐药肿瘤组织中上调。CTSLP8促进了OC细胞中DDP抗性的增殖和发展。此外，CTSLP8 通过促进 PKM2 与 c-Myc 启动子区域的结合来促进 c-Myc 表达，从而上调糖酵解。组织芯片分析显示，CTSLP8 的上调与 OC 患者 DDP 耐药和不良预后的发展有关。