Hsa_circ_0020095在类器官模型中调节结直肠癌的化疗耐药性。

Hsa_circ_0020095 modulates chemoresistance of CRC in a PDO model.

作者信息

Li Xinyu, Li Tao, Zhao Yan, Shan Junqi, Gao Yang, Zhou Changchun, Sun Yanlai

机构信息

School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China.

Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.

出版信息

Front Med (Lausanne). 2025 May 27;12:1556611. doi: 10.3389/fmed.2025.1556611. eCollection 2025.

DOI:10.3389/fmed.2025.1556611

PMID:40495972

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12148843/

Abstract

BACKGROUND

Colorectal cancer (CRC) is the third most common malignant tumor type all over the world with high mortality. Chemoresistance of CRC leads to treatment failure and disease aggravation. We previously identified Hsa_circ_0020095 as a novel oncogene to promote progression and cisplatin-resistance in colon cancers by modulating the miR-487a-3p/SOX9 axis.

METHODS

Patient-derived organoids (PDOs) were generated from CRC patients and validated by H&E staining, immunohistochemistry (IHC), and whole exome sequencing (WES). Hsa_circ_0020095 was knocked down in PDOs by shRNA and the inhibition of hsa_circ_0020095 was determined using RT-qPCR. The RNA samples analyzed separately, and then pooled together for KEGG and GO analyses. The effects of knocking down hsa_circ_0020095 on drug-resistance of PDOs were examined using CellTiter-Glo3D Cell viability assay. Finally, the underlying mechanism was explored by transcriptomic sequencing and subsequent bioinformatics analyses.

RESULTS

Five organoid lines were successfully established from CRC patients using surgically resected tumor samples. PDOs resembled their parental tumor tissues in morphology, histopathology, and genetic alterations. Silencing of circ_0020095 resulted in remarkable inhibition of hsa_circ_0020095 in PDOs and reversed the resistance of PDOs to 5-FU and oxaliplatin. Mechanistically, hsa_circ_0020095 may function by modulating key pathways and biological functions involved in pathophysiological processes in CRC.

CONCLUSION

Hsa_circ_0020095 modulates chemoresistance of CRC, which could potentially be explored as a therapeutic target for CRC treatment.

摘要

背景

结直肠癌（CRC）是全球第三大常见恶性肿瘤类型，死亡率高。CRC的化疗耐药导致治疗失败和疾病加重。我们之前鉴定出Hsa_circ_0020095是一种新型致癌基因，可通过调节miR-487a-3p/SOX9轴促进结肠癌进展和顺铂耐药。

方法

从CRC患者中生成患者来源的类器官（PDO），并通过苏木精和伊红（H&E）染色、免疫组织化学（IHC）和全外显子测序（WES）进行验证。通过短发夹RNA（shRNA）敲低PDO中的Hsa_circ_0020095，并使用逆转录定量聚合酶链反应（RT-qPCR）测定hsa_circ_0020095的抑制情况。对RNA样本进行单独分析，然后合并在一起进行京都基因与基因组百科全书（KEGG）和基因本体（GO）分析。使用CellTiter-Glo 3D细胞活力测定法检测敲低hsa_circ_0020095对PDO耐药性的影响。最后，通过转录组测序和后续生物信息学分析探索潜在机制。

结果

使用手术切除的肿瘤样本成功从CRC患者中建立了5种类器官系。PDO在形态、组织病理学和基因改变方面与其亲本肿瘤组织相似。circ_0020095的沉默导致PDO中hsa_circ_0020095受到显著抑制，并逆转了PDO对5-氟尿嘧啶（5-FU）和奥沙利铂的耐药性。从机制上讲，hsa_circ_0020095可能通过调节CRC病理生理过程中涉及的关键途径和生物学功能发挥作用。