Stiffness-related stress granules promote the metastasis of early-stage oral squamous cell carcinoma via anoikis resistance

BACKGROUND: Surgery is the first choice of treatment for oral squamous cell carcinoma (OSCC), including primary tumor resection and neck dissection. However, neck dissection of early-stage OSCC patients is still controversial. Exploration of mechanisms of early-stage OSCC metastasis might help to guide treatment choice. Our previous research has demonstrated that matrix stiffness activated the PERK-associated unfolded protein response (UPR), thereby contributing to early-stage OSCC metastasis. Since stress granules (SGs) are also regulated by PERK-mediated UPR, our study aimed to identify stiffness-related SGs and decipher their function of modulating early-stage OSCC metastasis. METHODS: At first, we evaluated matrix stiffness and SGs level in early-stage OSCC tissues. Then enhanced matrix stiffness was simulated in vivo and its effect on metastasis and SGs expression was observed. Furthermore, A force loading model was adopted to identify the stiffness-related SGs in vitro and the effects of stiffness-related SGs on metastasis were further evaluated in vitro and in vivo. We identified the unique type of SGs which was stiffness-related to adopt mechanical stimuli. The stiffness-related SGs may boost metastasis cascade through promotion of anoikis resistance. At last, we investigated the containing mRNAs of stiffness-related SGs through RNA Immunoprecipitation Sequencing. RESULTS: The stiffness-related SGs were identified which may boost metastasis cascade through promotion of anoikis resistance. The unique SGs were rich in mRNA related to negative regulation of apoptosis, partly explained the anoikis resistance associated with stiffness-related SGs. CONCLUSIONS: The stiffness-related SGs may protect the disseminated cancer cells from anoikis resistance by harboring the set of specific mRNAs. Matrix stiffness promotes the formation of SGs in OSCC, getting prepared for metastasis in the early stage.