HLF, also known as hepatic leukemia factor, is a master transcription factor with significant biological importance. It has been associated with multiple biological processes and disease-related pathways. In the hematopoietic system, it is proposed as one of the most specific marker genes for human hematopoietic stem cells (HSCs), playing a role in defining the HSC state [2]. In cancer, HLF is involved in various signaling pathways and has been linked to tumor progression and chemoresistance [1,3,4,5].

In triple-negative breast cancer (TNBC), HLF is regulated by TGF-β1 secreted by tumor-associated macrophages (TAMs). It transactivates GGT1 to promote ferroptosis resistance, cell proliferation, metastasis, and cisplatin resistance. TNBC cells reciprocally activate TAMs through IL-6, forming a feed-forward circuit [1]. In ovarian cancer, HLF upregulation promotes cancer progression and chemoresistance by transcriptionally activating YAP1 and modulating the Hippo signaling pathway. miR-520e negatively regulates HLF [3]. In intrahepatic cholangiocarcinoma, HLF activation mediated by METTL3-dependent m6A methylation promotes cancer progression through the FZD4/β-catenin signaling pathway [4]. In hepatocellular carcinoma, HLF, reactivated by SOX2 and OCT4, transactivates c-Jun to drive cancer development and sorafenib resistance [5].

In conclusion, HLF is a crucial factor in both normal hematopoietic development and cancer-related processes. Its role in promoting tumor progression and chemoresistance in various cancers such as TNBC, ovarian cancer, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma highlights its potential as a therapeutic target. Research on HLF using in vivo models has provided valuable insights into its functions and the associated disease mechanisms [1,3,4,5].

References:

1. Li, Hengyu, Yang, Pinghua, Wang, JingHan, Han, Tao, Xiang, Daimin. 2022. HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk. In Journal of hematology & oncology, 15, 2. doi:10.1186/s13045-021-01223-x. https://pubmed.ncbi.nlm.nih.gov/34991659/

2. Lehnertz, Bernhard, Chagraoui, Jalila, MacRae, Tara, Gracias, Deanne, Sauvageau, Guy. . HLF expression defines the human hematopoietic stem cell state. In Blood, 138, 2642-2654. doi:10.1182/blood.2021010745. https://pubmed.ncbi.nlm.nih.gov/34499717/

3. Han, Tao, Chen, Tingsong, Chen, Lujun, Li, Hengyu, Gu, Yubei. 2023. HLF promotes ovarian cancer progression and chemoresistance via regulating Hippo signaling pathway. In Cell death & disease, 14, 606. doi:10.1038/s41419-023-06076-5. https://pubmed.ncbi.nlm.nih.gov/37709768/

4. Xiang, Daimin, Gu, Mingye, Liu, Junyu, Fu, Jing, Wang, Hongyang. 2023. m6A RNA methylation-mediated upregulation of HLF promotes intrahepatic cholangiocarcinoma progression by regulating the FZD4/β-catenin signaling pathway. In Cancer letters, 560, 216144. doi:10.1016/j.canlet.2023.216144. https://pubmed.ncbi.nlm.nih.gov/36958694/

5. Xiang, Dai-Min, Sun, Wen, Zhou, Tengfei, Wang, Hongyang, Ding, Jin. 2019. Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance. In Gut, 68, 1858-1871. doi:10.1136/gutjnl-2018-317440. https://pubmed.ncbi.nlm.nih.gov/31118247/