CA916798 预示肺腺癌不良预后并促进吉非替尼耐药。

CA916798 predicts poor prognosis and promotes Gefitinib resistance for lung adenocarcinoma.

机构信息

Department of Respiratory medicine, The First Hospital Affiliated to Army Medical University, 29 Gaotanyan Main Street, Chongqing, 400038, China.

Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.

出版信息

BMC Cancer. 2023 Mar 23;23(1):266. doi: 10.1186/s12885-023-10735-3.

DOI:10.1186/s12885-023-10735-3

PMID:36959566

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10035219/

Abstract

BACKGROUND

Our previous studies have identified CA916798 as a chemotherapy resistance-associated gene in lung cancer. However, the histopathological relevance and biological function of CA916798 in lung adenocarcinoma (LUAD) remains to be delineated. In this study, we further investigated and explored the clinical and biological significance of CA916798 in LUAD.

METHODS

The relationship between CA916798 and clinical features of LUAD was analyzed by tissue array and online database. CCK8 and flow cytometry were used to measure cell proliferation and cell cycle of LUAD after knockdown of CA916798 gene. qRT-PCR and western blotting were used to detect the changes of cell cycle-related genes after knockdown or overexpression of CA916798. The tumorigenesis of LUAD cells was evaluated with or without engineering manipulation of CA916798 gene expression. Response to Gefitinib was evaluated using LUAD cells with forced expression or knockdown of CA916798.

RESULTS

The analysis on LUAD samples showed that high expression of CA916798 was tightly correlated with pathological progression and poor prognosis of LUAD patients. A critical methylation site in promoter region of CA916798 gene was identified to be related with CA916798 gene expression. Forced expression of CA916798 relieved the inhibitory effects of WEE1 on CDK1 and facilitated cell cycle progression from G2 phase to M phase. However, knockdown of CA916798 enhanced WEE1 function and resulted in G2/M phase arrest. Consistently, chemical suppression of CDK1 dramatically inhibited G2/M phase transition in LUAD cells with high expression of CA916798. Finally, we found that CA916798 was highly expressed in Gefitinib-resistant LUAD cells. Exogenous expression of CA916798 was sufficient to endow Gefitinib resistance with tumor cells, but interference of CA916798 expression largely rescued response of tumor cells to Gefitinib.

CONCLUSIONS

CA916798 played oncogenic roles and was correlated with the development of Gefitinib resistance in LUAD cells. Therefore, CA916798 could be considered as a promising prognostic marker and a therapeutic target for LUAD.

摘要

背景

我们之前的研究已经确定 CA916798 是肺癌化疗耐药相关基因。然而，CA916798 在肺腺癌（LUAD）中的组织病理学相关性和生物学功能仍有待阐明。在这项研究中，我们进一步研究和探讨了 CA916798 在 LUAD 中的临床和生物学意义。

方法

通过组织阵列和在线数据库分析 CA916798 与 LUAD 临床特征的关系。用 CCK8 和流式细胞术检测 CA916798 基因敲低后 LUAD 细胞的增殖和细胞周期。用 qRT-PCR 和 Western blot 检测 CA916798 基因敲低或过表达后细胞周期相关基因的变化。通过 CA916798 基因表达的工程操作来评估 LUAD 细胞的肿瘤发生。用 LUAD 细胞强制表达或敲低 CA916798 来评估对 Gefitinib 的反应。

结果

对 LUAD 样本的分析表明，CA916798 的高表达与 LUAD 患者的病理进展和预后不良密切相关。鉴定出 CA916798 基因启动子区域的一个关键甲基化位点与 CA916798 基因表达有关。CA916798 的强制表达缓解了 WEE1 对 CDK1 的抑制作用，并促进了细胞周期从 G2 期向 M 期的进展。然而，CA916798 的敲低增强了 WEE1 的功能，导致 G2/M 期阻滞。一致地，化学抑制 CDK1 可显著抑制高表达 CA916798 的 LUAD 细胞的 G2/M 期转换。最后，我们发现 CA916798 在 Gefitinib 耐药的 LUAD 细胞中高表达。CA916798 的外源性表达足以赋予肿瘤细胞对 Gefitinib 的耐药性，但干扰 CA916798 的表达则大大挽救了肿瘤细胞对 Gefitinib 的反应。