Hspa4, also known as Heat shock 70 kDa protein 4, is a member of the HSP110 family. It has been implicated in various biological processes and is associated with the PI3K/Akt signaling pathway [2,3]. Hspa4 plays a role in protein folding and quality control, which is crucial for cell survival and normal cellular functions [1-6]. Genetic models, such as gene knockout (KO) in cell lines and animal models, can be used to study its functions in depth.

In cancer, Hspa4 shows significant associations. In colorectal cancer, Hspa4 knockdown inhibited proliferation, migration, arrested the cell cycle in G2-phase, and increased apoptosis, also suppressing xenograft growth in vivo. This was accompanied by reduced activation of the PI3K/Akt signaling axis and down-regulation of cell cycle progression markers [2]. In glioma, in vitro knockdown of Hspa4 inhibited cell proliferation, mediated cell cycle arrest at G2 phase, apoptosis, and reduced migration ability, and in vivo, it suppressed xenograft growth. Gene set enrichment analyses disclosed its association with the PI3K/Akt signaling pathway [3]. In melanoma, knocking down Hspa4 in A-375 cell line could inhibit tumor cell growth, and high expression of Hspa4 was associated with poor prognosis [4]. In hepatocellular carcinoma, overexpression of Hspa4 was correlated with cancer stage and AFP level, and patients with higher Hspa4 expression had poorer prognosis. Hspa4 was also positively related to immune cell infiltration and immune checkpoints (PD-1 and CTLA-4) [6]. In gastric cancer, Hspa4 up-regulation causes immune evasion via the HSPA4/ALKBH5/CD58 axis, leading to PD1/PDL1 activation and impairment of CD8+ T cell's cytotoxicity [1]. In breast cancer, high serum anti-HSPA4 IgG was correlated with high tumor HSPA4 expression and poor prognosis [5].

In summary, Hspa4 plays crucial roles in cancer development, progression, and immune regulation, as revealed through in vitro and in vivo functional studies. The use of KO models in cell lines and animal models has provided valuable insights into its role in specific disease areas such as colorectal cancer, glioma, melanoma, hepatocellular carcinoma, gastric cancer, and breast cancer.

References:

1. Suo, Daqin, Gao, Xiaoling, Chen, Qingyun, Guan, Xin-Yuan, Li, Yan. 2024. HSPA4 upregulation induces immune evasion via ALKBH5/CD58 axis in gastric cancer. In Journal of experimental & clinical cancer research : CR, 43, 106. doi:10.1186/s13046-024-03029-4. https://pubmed.ncbi.nlm.nih.gov/38589927/

2. Zhang, Mingliang, Dai, Weigang, Li, Zhanyu, Chen, Jianhui, Chen, Chuangqi. 2021. HSPA4 Knockdown Retarded Progression and Development of Colorectal Cancer. In Cancer management and research, 13, 4679-4690. doi:10.2147/CMAR.S310729. https://pubmed.ncbi.nlm.nih.gov/34163243/

3. Yuan, Xi, Sun, Xiangdong, Zhou, Bin, Li, Yikun, Ming, Haolang. 2023. HSPA4 regulated glioma progression via activation of AKT signaling pathway. In Biochemistry and cell biology = Biochimie et biologie cellulaire, 102, 159-168. doi:10.1139/bcb-2022-0321. https://pubmed.ncbi.nlm.nih.gov/37339521/

4. Wang, Xudong, Li, Zhiyong, Xu, Jianhong, Niu, Jianrong, Yang, Rongya. 2024. HSPA4 Expression is Correlated with Melanoma Cell Proliferation, Prognosis, and Immune Regulation. In Clinical, cosmetic and investigational dermatology, 17, 2733-2746. doi:10.2147/CCID.S477870. https://pubmed.ncbi.nlm.nih.gov/39629045/

5. Gu, Yan, Liu, Yanfang, Fu, Li, Zhang, Xiang, Cao, Xuetao. 2019. Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG. In Nature medicine, 25, 312-322. doi:10.1038/s41591-018-0309-y. https://pubmed.ncbi.nlm.nih.gov/30643287/

6. Shang, Bing-Bing, Chen, Jun, Wang, Zhi-Guo, Liu, Hui. 2021. Significant correlation between HSPA4 and prognosis and immune regulation in hepatocellular carcinoma. In PeerJ, 9, e12315. doi:10.7717/peerj.12315. https://pubmed.ncbi.nlm.nih.gov/34754620/