AGR2, or anterior gradient-2, is a 20 kDa secreted protein widely existing in breast and other tissues. It plays a crucial role in facilitating the formation of protein disulfide bonds within the endoplasmic reticulum (ER) and contributes to the homeostasis of the secretory pathway. AGR2 is involved in several signal transduction pathways essential for cell survival and has been associated with embryonic development [3,4,6]. Gene knockout and conditional knockout mouse models have been valuable in uncovering its functions.

In a neutrophil-specific Agr2 knockout (Agr2f/f;Mrp-Cre) mouse model, neutrophil-specific ablation of Agr2 ameliorated CRC liver metastases, indicating that tumour-associated neutrophils (TANs)-secreted AGR2 promotes CRC cells' migration [1]. In breast cancer, LINC02273-hnRNPL complex epigenetically upregulates AGR2 by augmenting local H3K4me3 and H3K27ac levels, promoting breast cancer metastasis [2]. Also, intracellular AGR2 in CRC binds to KDEL receptors via its KTEL motif to activate downstream Gs-PKA signaling, promoting epithelial-mesenchymal transition and metastasis [5].

In conclusion, AGR2 is important for protein disulfide bond formation and secretory pathway homeostasis. Model-based research, especially using Agr2 KO/CKO mouse models, has revealed its significant role in promoting metastasis in colorectal and breast cancers. Understanding AGR2's functions provides potential targets for cancer treatment and prognosis prediction.

References:

1. Tian, Shaobo, Chu, Yanan, Hu, Jia, Wang, Lin, Wang, Zheng. 2022. Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc-xCT. In Gut, 71, 2489-2501. doi:10.1136/gutjnl-2021-325137. https://pubmed.ncbi.nlm.nih.gov/35086885/

2. Xiu, Bingqiu, Chi, Yayun, Liu, Lei, Huang, Shenglin, Wu, Jiong. 2019. LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription. In Molecular cancer, 18, 187. doi:10.1186/s12943-019-1115-y. https://pubmed.ncbi.nlm.nih.gov/31856843/

3. Qu, Shen, Jia, Weili, Nie, Ye, Zhao, Zihao, Song, Wenjie. 2024. AGR2: The Covert Driver and New Dawn of Hepatobiliary and Pancreatic Cancer Treatment. In Biomolecules, 14, . doi:10.3390/biom14070743. https://pubmed.ncbi.nlm.nih.gov/39062458/

4. Moidu, Nurshahirah Ashikin, A Rahman, Nisa Syakila, Syafruddin, Saiful Effendi, Low, Teck Yew, Mohtar, M Aiman. 2020. Secretion of pro-oncogenic AGR2 protein in cancer. In Heliyon, 6, e05000. doi:10.1016/j.heliyon.2020.e05000. https://pubmed.ncbi.nlm.nih.gov/33005802/

5. Zhang, Hongyan, Chi, Jiangyang, Hu, Jia, Wang, Lin, Wang, Zheng. 2021. Intracellular AGR2 transduces PGE2 stimuli to promote epithelial-mesenchymal transition and metastasis of colorectal cancer. In Cancer letters, 518, 180-195. doi:10.1016/j.canlet.2021.06.025. https://pubmed.ncbi.nlm.nih.gov/34216690/

6. Jach, Daria, Cheng, Yuzhu, Prica, Filip, Dumartin, Laurent, Crnogorac-Jurcevic, Tatjana. 2021. From development to cancer - an ever-increasing role of AGR2. In American journal of cancer research, 11, 5249-5262. doi:. https://pubmed.ncbi.nlm.nih.gov/34873459/