Hoxa4, a member of the homeobox gene family, has diverse functions. It is involved in embryonic development, such as patterning the mouse lung during embryogenesis, and has been associated with hematopoietic stem cell (HSC) self-renewal and expansion [2,3,6]. It may also play roles in cell-cycle regulation, adhesion, and signaling pathways like JAK/STAT, Wnt, and Notch [1,2,3]. Genetic models, especially KO/CKO mouse models, could potentially offer insights into its precise functions.

In glioma, high Hoxa4 mRNA levels are associated with unfavorable clinical outcomes, and knockdown of Hoxa4 inhibits cell proliferation, invasion, and chemotherapy resistance, blocking the cell-cycle pathway [1]. In lung cancer, its down-regulation is observed, and overexpression suppresses cell growth, migration, and invasion by inhibiting the Wnt signaling pathway [2]. In LUAD, both Hoxa4 and Hoxa5 are down-expressed, and Hoxa4 overexpression inhibits cell proliferation, migration, and invasion [4]. In non-small cell lung cancer, Hoxa4-regulated miR-138 suppresses cell proliferation and gefitinib resistance [5]. In hematopoiesis, HOXA4-transduced HSCs and primitive progenitors expand in culture, and in vivo, it enhances pro-B-cells [6]. In the heart, Hoxa4 is upregulated in patients with heart failure and in cardiac fibroblasts under hypoxia/reoxygenation, and its deficiency protects the heart from myocardial infarction [7].

In conclusion, Hoxa4 is involved in multiple biological processes and diseases. Studies using genetic models, although not always directly from KO/CKO mouse models in the provided references, suggest its significance in cancer (glioma, lung cancer, LUAD, non-small cell lung cancer), hematopoiesis, and heart-related conditions. Understanding Hoxa4's functions through these models can potentially lead to new diagnostic and therapeutic strategies for these diseases.

References:

1. Yu, Zhenghong, Liu, Zhendong, Lian, Xiaoyu, Qian, Rongjun, Gao, Yanzheng. 2022. High expression of HOXA4 in patients with glioma indicates unfavorable clinical outcomes. In Cell cycle (Georgetown, Tex.), 21, 2387-2402. doi:10.1080/15384101.2022.2096715. https://pubmed.ncbi.nlm.nih.gov/35852388/

2. Cheng, Shaofei, Qian, Fengying, Huang, Qin, Fu, Yawen, Du, Yuzhen. 2018. HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells. In Cell death & disease, 9, 465. doi:10.1038/s41419-018-0497-x. https://pubmed.ncbi.nlm.nih.gov/29700285/

3. Fournier, Marilaine, Lebert-Ghali, Charles-Étienne, Bijl, Janetta J. 2015. HOXA4 provides stronger engraftment potential to short-term repopulating cells than HOXB4. In Stem cells and development, 24, 2413-22. doi:10.1089/scd.2015.0063. https://pubmed.ncbi.nlm.nih.gov/26166023/

4. Gao, Li, He, Rong-Quan, Huang, Zhi-Guang, Feng, Zhen-Bo, Chen, Gang. 2022. Expression Landscape and Functional Roles of HOXA4 and HOXA5 in Lung Adenocarcinoma. In International journal of medical sciences, 19, 572-587. doi:10.7150/ijms.70445. https://pubmed.ncbi.nlm.nih.gov/35370463/

5. Tang, Xiaomei, Jiang, Jiying, Zhu, Jinbao, He, Nan, Tan, Jinlong. 2018. HOXA4-regulated miR-138 suppresses proliferation and gefitinib resistance in non-small cell lung cancer. In Molecular genetics and genomics : MGG, 294, 85-93. doi:10.1007/s00438-018-1489-3. https://pubmed.ncbi.nlm.nih.gov/30196354/

6. Fournier, Marilaine, Lebert-Ghali, Charles-Étienne, Krosl, Gorazd, Bijl, Janet J. 2011. HOXA4 induces expansion of hematopoietic stem cells in vitro and confers enhancement of pro-B-cells in vivo. In Stem cells and development, 21, 133-42. doi:10.1089/scd.2011.0259. https://pubmed.ncbi.nlm.nih.gov/21749220/

7. Aonuma, Tatsuya, Moukette, Bruno, Kawaguchi, Satoshi, Nakagawa, Shinichi, Kim, Il-Man. 2022. MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic Hoxa4. In Circulation. Heart failure, 15, e008686. doi:10.1161/CIRCHEARTFAILURE.121.008686. https://pubmed.ncbi.nlm.nih.gov/35000421/