Exosomal S100A4 derived from highly metastatic hepatocellular carcinoma cells promotes metastasis by activating STAT3

Abstract

Intercellular cross-talk plays important roles in cancer progression and metastasis. Yet how these cancer cells interact with each other is still largely unknown. Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators. We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma (HCC). Exosomes were extracted from HCC cells of different metastatic potentials. The metastatic effects of exosomes derived from highly metastatic HCC cells (HMH) were evaluated both in vitro and in vivo. Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines, xenograft tumor samples, and functional analyses. Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells (LMH). S100 calcium-binding protein A4 (S100A4) was identified as a functional factor in exosomes derived from HMH. S100A4rich exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4low exosomes or controls. Moreover, exosomal S100A4 could induce expression of osteopontin (OPN), along with other tumor metastasis/stemness-related genes. Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation. HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis. In conclusion, exosomes from HMH could promote the metastatic potential of LMH, and exosomal S100A4 is a key enhancer for HCC metastasis, activating STAT3 phosphorylation and up-regulating OPN expression. This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.

Targeted protein degradation: mechanisms, strategies and application

“…Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in a variety of human cancers. 114 – 118 Small-molecule inhibitors targeting the STAT3 SH2 domain have selectivity problems and show very limited clinical activity. Recently, a potent and specific PROTAC degrader of STAT3, SD-36, was developed.…”

Tumor-Derived Extracellular Vesicles Regulate Cancer Progression in the Tumor Microenvironment

“…Recent studies have found that tumor-derived EVs may be a potential biomarker for cancer prognosis ( Table 3 ). For instance, highly expressed vesicular S100A4 and osteopontin are related to short overall survival rates and disease free survival rates in HCC patients ( Sun et al, 2021 ). Similarly, highly expressed vesicular lncRNA-SOX2OT are also related to short overall survival rates in NSCLC patients ( Ni et al, 2021 ).…”

A Novel Epithelial-Mesenchymal Transition Gene Signature Correlated With Prognosis, and Immune Infiltration in Hepatocellular Carcinoma

“…Over the years, exosome-related proteins, miRNAs, lncRNAs, and circRNAs have been extensively studied as prognostic markers for HCC patients ( Zhang et al, 2021 ). For example, Sun et al demonstrated that S100A4 carried by exosomes in the plasma of HCC patients could promote HCC metastasis, thereby affecting patient OS and DFS ( Sun et al, 2021 ). Compared with our constructed EMT-gene signature, both CAFs and exosomes could be used as prognostic indicators for HCC patients.…”