Shc4, also known as ShcD, is an intracellular adaptor protein belonging to the Shc family. It plays crucial roles in various signaling pathways, such as those related to cancer metastasis and cell proliferation. Shc4 has been implicated in pathways like β-catenin and STAT3 signaling, highlighting its importance in biological processes related to tumorigenesis [1,2].

In triple-negative breast cancer (TNBC), overexpression of SHC4 promoted aggressiveness in vitro and metastasis in vivo. It interacted with Src, maintaining its autophosphorylated activation, which activated β-catenin independent of Wnt signaling, upregulating downstream genes CD44 and MMP7 [1]. In hepatocellular carcinoma, SHC4 overexpression enhanced cell proliferation, migration, invasion, and promoted cell cycle progression and EMT. It activated STAT3 signaling, which was confirmed as an important pathway for its oncogenic role [2]. In glioma, ShcD (SHC4) interacted with Tie2 receptor to promote glioma cell invasion, and its elevated expression correlated with poor patient outcome in advanced gliomas [3]. In prostate cancer cells, miR-26a regulated extracellular vesicle secretion by targeting SHC4, and suppressing SHC4 inhibited PCa progression in vivo [4].

In conclusion, Shc4 is a significant adaptor protein involved in multiple cancer-related biological processes. Through in vivo studies and functional studies, its role in promoting tumor progression in various cancers such as TNBC, hepatocellular carcinoma, glioma, and prostate cancer has been revealed. Understanding Shc4's functions provides potential prognostic markers and therapeutic targets for these diseases.

References:

1. Zhong, Wenjing, Jian, Yunting, Zhang, Chao, Liu, Pian, Wang, Xi. 2023. SHC4 orchestrates β-catenin pathway-mediated metastasis in triple-negative breast cancer by promoting Src kinase autophosphorylation. In Cancer letters, 582, 216516. doi:10.1016/j.canlet.2023.216516. https://pubmed.ncbi.nlm.nih.gov/38052369/

2. Zhang, Xin, Zhang, Hongwei, Liao, Zhibin, Yu, Jia, Dong, Keshuai. 2022. SHC4 promotes tumor proliferation and metastasis by activating STAT3 signaling in hepatocellular carcinoma. In Cancer cell international, 22, 24. doi:10.1186/s12935-022-02446-9. https://pubmed.ncbi.nlm.nih.gov/35033067/

3. Tilak, Manali, Alural, Begüm, Wismer, Sarah E, Lalonde, Jasmin, Jones, Nina. 2021. Adaptor Protein ShcD/SHC4 Interacts with Tie2 Receptor to Synergistically Promote Glioma Cell Invasion. In Molecular cancer research : MCR, 19, 757-770. doi:10.1158/1541-7786.MCR-20-0188. https://pubmed.ncbi.nlm.nih.gov/33495401/

4. Urabe, Fumihiko, Kosaka, Nobuyoshi, Sawa, Yurika, Egawa, Shin, Ochiya, Takahiro. 2020. miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4, and CHORDC1. In Science advances, 6, eaay3051. doi:10.1126/sciadv.aay3051. https://pubmed.ncbi.nlm.nih.gov/32494663/