雌激素受体阴性乳腺癌中与缺氧相关的失调通路的阐释

Elucidation of Dysregulated Pathways Associated With Hypoxia in Oestrogen Receptor-Negative Breast Cancer.

作者信息

Shamis Suad A K, Quinn Jean, Al-Badran Sara, McKenzie Molly, Hatthakarnkul Phimmada, Lynch Gerard, Lian Guang-Yu, Numprasit Warapan, Romics Laszlo, Andersen Ditte, Mallon Elizabeth, McMillan Donald C, Edwards Joanne

机构信息

Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, UK.

Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, UK.

出版信息

Cancer Med. 2024 Dec;13(23):e70274. doi: 10.1002/cam4.70274.

DOI:10.1002/cam4.70274

PMID:39660488

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11632397/

Abstract

PURPOSE

Carbonic anhydrase IX (CAIX) is a well-established prognostic marker in breast cancer (BC). Nevertheless, this prognostic value is yet to be confirmed in BC subtypes. This study aims to investigate the prognostic effects of CAIX in oestrogen receptor (ER)-negative (ER-) BCs and to establish pathways related to cytoplasmic CAIX expression in ER- and lymph node-negative BCs.

METHODS

Immunohistochemistry was performed to identify the prognostic role of CAIX protein expression in ER- tissue microarrays (TMAs) (n = 191). CAIX-positive samples (n = 37) were transcriptionally profiled by TempO-Seq and analysed by STRING. Real-time quantitative PCR (RT-qPCR) analysis was used to validate differentially expressed genes.

RESULTS

Overexpression of cytoplasmic CAIX was an independent predictor of recurrence free survival, disease-free survival and overall survival in ER- cohort. RNA transcriptomic analysis identified 10 significant genes in ER- cohort and 3 genes in the node-negative group. The STRING database demonstrated a significant interaction between MUCL1 and GALNT6, which were linked with extracellular matrix organisation, degradation of the extracellular matrix and disease of glycosylation pathways. In the node-negative group, SPNS2 is mainly involved in the sphingolipid de novo biosynthesis pathway. A significant correlation between cytoplasmic SphK1 and cytoplasmic hypoxia-inducible factor-1α was observed. Among the 10 genes, 7 genes (SERHL2, GALNT6, MUCL1, MMP7, PITX2, CEACAM6 and SPNS2) were selected, and their expression was quantitatively assessed by RT-qPCR. The PCR data of these genes showed that SERHL2, GALNT6, MUCL1, PITX2, and SPNS2 mRNA levels were expressed in MDA-MB-231 BC cell lines at variable levels of hypoxic exposure.

CONCLUSION

Cytoplasmic CAIX was independently associated with poor prognosis in ER- BC. Gene expression profiles shed light on the pathways and genes associated with hypoxia in ER- BC. In node-negative patients, SPNS2 was of particular interest.

摘要

目的

碳酸酐酶IX（CAIX）是乳腺癌（BC）中公认的预后标志物。然而，这种预后价值尚未在BC亚型中得到证实。本研究旨在探讨CAIX在雌激素受体（ER）阴性（ER-）BC中的预后作用，并建立与ER和淋巴结阴性BC中细胞质CAIX表达相关的途径。

方法

采用免疫组织化学法确定CAIX蛋白表达在ER-组织微阵列（TMA）（n = 191）中的预后作用。对CAIX阳性样本（n = 37）进行TempO-Seq转录谱分析，并通过STRING进行分析。采用实时定量PCR（RT-qPCR）分析验证差异表达基因。

结果

细胞质CAIX的过表达是ER-队列中无复发生存、无病生存和总生存的独立预测因子。RNA转录组分析在ER-队列中鉴定出10个显著基因，在淋巴结阴性组中鉴定出3个基因。STRING数据库显示MUCL1和GALNT6之间存在显著相互作用，它们与细胞外基质组织、细胞外基质降解和糖基化途径疾病有关。在淋巴结阴性组中，SPNS2主要参与鞘脂从头生物合成途径。观察到细胞质鞘氨醇激酶1（SphK1）与细胞质缺氧诱导因子-1α之间存在显著相关性。在这10个基因中，选择了7个基因（SERHL2、GALNT6、MUCL1、MMP7、PITX2、CEACAM6和SPNS2），并通过RT-qPCR对其表达进行定量评估。这些基因的PCR数据表明，SERHL2、GALNT6、MUCL1、PITX2和SPNS2的mRNA水平在不同程度缺氧暴露的MDA-MB-231 BC细胞系中表达。