Annexin A4 (encoded by the ANXA4 gene) is a calcium ion (Ca²⁺)- and phospholipid-binding protein of the Annexin family. In this study, we checked the expression profile of ANXA4 in basal-like breast cancer (BLBC) and its association with survival outcomes using pan-cancer data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project. Then, using MDA-MB-231 and MDA-MB-468 cells, we explored the functional role of ANXA4 in regulating a cancer-related signaling pathway and identified potential partners of ANXA4. The results showed that expression of total ANXA4 and the two dominant ANXA4 protein-coding transcripts (ENST00000409920.5 and ENST00000394295.4) was consistently upregulated in tumor tissues compared with normal breast tissues. BLBC patients with high ANXA4 expression had significantly worse overall survival, progression-free survival, and disease-free survival than those with low ANXA4 expression. ANXA4 could positively modulate cyclin D1 expression and G1/S progression in the two cell lines. An in vivo tumor model showed that ANXA4 inhibition significantly slowed the growth of tumors derived from the two BLBC cell lines. ANXA4 could increase JAK1 expression and STAT3 phosphorylation (Y705). ANXA4 colocalized with ANXA1 in some MDA-MB-231 cells. A co-immunoprecipitation assay confirmed direct binding between ANXA4 and ANXA1. Knockdown of ANXA1 reduced JAK1 expression and STAT3 phosphorylation and impaired ANXA4-induced upregulation of JAK1 and p-STAT3. In conclusion, this study revealed that aberrant ANXA4 upregulation is associated with poor survival in BLBC. ANXA4 could activate JAK-STAT3 signaling by elevating the expression of JAK1 and p-STAT3, which was mediated by direct interaction with ANXA1.

中文翻译：

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ANXA4通过与ANXA1相互作用来激活基础类乳腺癌中的JAK-STAT3信号。

Annexin A4（由ANXA4基因编码）是Annexin家族的钙离子（Ca ²⁺）和磷脂结合蛋白。在这项研究中，我们使用了癌基因组图谱（TCGA）和基因型组织表达（GTEx）项目的全癌数据，检查了ANXA4在基底样乳腺癌（BLBC）中的表达谱及其与生存结果的关系。然后，我们使用MDA-MB-231和MDA-MB-468细胞探索了ANXA4在调节癌症相关信号通路中的功能，并确定了ANXA4的潜在伴侣。结果表明总ANXA4的表达与正常乳腺组织相比，肿瘤组织中两个主要的ANXA4蛋白编码转录本（ENST00000409920.50.5和ENST00000394295.4）始终被上调。高ANXA4表达的BLBC患者比低ANXA4表达的患者的总生存率，无进展生存率和无病生存率明显差。ANXA4可以正调控两个细胞系中细胞周期蛋白D1的表达和G1 / S的进程。的体内肿瘤模型中显示，ANXA4抑制作用显着减慢了来自两种BLBC细胞系的肿瘤的生长。ANXA4可以增加JAK1表达和STAT3磷酸化（Y705）。在某些MDA-MB-231细胞中，ANXA4与ANXA1共定位。免疫共沉淀试验证实了ANXA4和ANXA1之间的直接结合。敲低ANXA1会降低JAK1表达和STAT3磷酸化，并削弱ANXA4诱导的JAK1和p-STAT3的上调。总之，这项研究表明异常的ANXA4上调与BLBC的不良生存有关。ANXA4可以通过提高JAK1和p-STAT3的表达来激活JAK-STAT3信号，这是由与ANXA1的直接相互作用介导的。