A novel ITGB8 transcript variant sustains ovarian cancer cell survival through genomic instability and altered ploidy on a mutant p53 background.

IF 3.8 3区医学 Q1 REPRODUCTIVE BIOLOGY

Journal of Ovarian Research Pub Date : 2024-11-06 DOI:10.1186/s13048-024-01538-6

Aravindan Narayanan, Ankita S More, Muskan Talreja, Avinash M Mali, Sannannagari Boya Vinay, Sharmila A Bapat

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引用次数: 0

Abstract

Background: Transcript variants and protein isoforms are central to unique tissue functions and maintenance of homeostasis, in addition to being associated with aberrant states such as cancer, where their crosstalk with the mutated tumor suppressor p53 may contribute to genomic instability and chromosomal rearrangements. We previously identified several novel splice variants in ovarian cancer RNA-sequencing datasets; herein, we aimed to elucidate the biological effects of the Integrin Subunit Beta 8 variant (termed pITGB8-205).

Methods: Resolution of the full-length sequence of pITGB8-205 through rapid amplification of cDNA ends (RACE-PCR). Cell cycle analysis and karyotype studies were performed to further explore genomic instability. RNA-seq and proteomics analyses were used to identify the differential expression of the genes.

Results: This full-length study revealed a unique 5' sequence in pITGB8-205 that differed from the reported ITGB8-205 sequence, suggesting differential regulation of this novel transcript. Under a p53 mutant background, overexpression of pITGB8-205 triggered genetic instability reminiscent of oncogene-induced replicative stress with extensive abnormal mitoses and chromosomal and nuclear aberrations indicative of chromosomal instability, leading to near whole-genome duplication that imposes energy stress on cellular resources. Micronuclei and aneuploidy are striking features of pITGB8-205-overexpressing p53-mutant cells but are not enhanced in p53 wild-type (WT) cells. RNA-seq and proteomics analyses further suggested that p53 inactivation in ovarian cancer provides a permissive intracellular molecular niche for pITGB8-205 to mediate its effects on genomic instability. This observation is pivotal considering that most high-grade serous ovarian carcinoma (HGSC) tumors express mutant p53. The resulting aneuploid clones with enhanced self-renewal and survival capabilities disrupt clonal dominance under stress yet maintain a balance between replicative stress and prosurvival advantages.

Conclusion: pITGB8-205-overexpressing clones sustain ovarian tumor cell survival, achieve homeostasis and are formidable opponents of therapy.

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一种新型 ITGB8 转录本变体通过基因组不稳定性和倍性改变维持突变 p53 背景下卵巢癌细胞的存活。

背景：转录物变体和蛋白质同工酶是独特组织功能和维持体内平衡的核心，此外还与癌症等异常状态有关，它们与突变的肿瘤抑制因子 p53 之间的串扰可能会导致基因组不稳定和染色体重排。我们之前在卵巢癌 RNA 序列数据集中发现了几种新型剪接变体；在此，我们旨在阐明整合素亚基 Beta 8 变体（称为 pITGB8-205）的生物学效应：方法：通过 cDNA 末端快速扩增（RACE-PCR）解析 pITGB8-205 的全长序列。进行细胞周期分析和核型研究以进一步探索基因组的不稳定性。RNA-seq 和蛋白质组学分析用于确定基因的差异表达：这项全长研究揭示了pITGB8-205中独特的5'序列，该序列与报道的ITGB8-205序列不同，表明这种新型转录本存在不同的调控。在 p53 突变体背景下，pITGB8-205 的过表达引发了遗传不稳定性，这与癌基因诱导的复制压力相似，具有广泛的异常有丝分裂以及染色体和核畸变，表明染色体不稳定，导致近乎全基因组复制，对细胞资源造成能量压力。微核和非整倍体是 pITGB8-205 过表达 p53 突变细胞的显著特征，但在 p53 野生型（WT）细胞中并没有增强。RNA-seq和蛋白质组学分析进一步表明，卵巢癌中的p53失活为pITGB8-205介导其对基因组不稳定性的影响提供了一个有利的细胞内分子生态位。考虑到大多数高级别浆液性卵巢癌（HGSC）都表达突变的 p53，这一观察结果至关重要。结论：pITGB8-205 高表达克隆可维持卵巢肿瘤细胞的存活，实现体内平衡，是治疗的强大对手。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Ovarian Research REPRODUCTIVE BIOLOGY-

CiteScore

6.20

自引率

2.50%

发文量

125

审稿时长

>12 weeks

期刊介绍： Journal of Ovarian Research is an open access, peer reviewed, online journal that aims to provide a forum for high-quality basic and clinical research on ovarian function, abnormalities, and cancer. The journal focuses on research that provides new insights into ovarian functions as well as prevention and treatment of diseases afflicting the organ. Topical areas include, but are not restricted to: Ovary development, hormone secretion and regulation Follicle growth and ovulation Infertility and Polycystic ovarian syndrome Regulation of pituitary and other biological functions by ovarian hormones Ovarian cancer, its prevention, diagnosis and treatment Drug development and screening Role of stem cells in ovary development and function.