SQSTM1/p62 regulate breast cancer progression and metastasis by inducing cell cycle arrest and regulating immune cell infiltration

The autophagy adaptor protein SQSTM1/p62 is overexpressed in breast cancer and has been identified as a metastasis-related protein. However, the mechanism by which SQSTM1/p62 contributes to breast cancer progression and tumor microenvironment remains unclear. This study revealed that silencing SQSTM1/p62 expression suppressed breast cancer progression via regulating cell proliferation and reshaping the tumor microenvironment (TME). Here, we found that SQSTM1/p62 was overexpressed in multiple human cancer tissue types and that was correlated with poor patient overall survival (OS) and disease-free survival (DFS). Moreover, we found that short-hairpin RNA (shRNA)-mediated knockdown of p62 expres-sion significantly inhibited cell proliferation, migration, and invasion, and promoted cell death in vitro, as well as suppressed breast cancer growth and lung metastasis in vivo. In addition, flow cytometry analysis of splenocytes and tumor infiltrating lymphocytes (TILs) indicated that the numbers of CD8a+ interferon (IFN)-gamma(+) cells (CTLs) and CD4(+)IFN-gamma(+) (Th1) cells were increased while those of CD4+IL-4(+) (Th2) cells, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) were decreased. RT-PCR analyses showed that the gene expression of Th1/Th2 cytokines changed in the tumor microenvironment. Silencing SQSTM1/p62 suppressed tumor cell lung metastasis. Together, our results provide strong evi-dence that silencing tumor cell SQSTM1/p62 inhibited tumor growth and metastasis through cell cycle arrest and TME regulation. This finding provides a novel molecular therapeutic strat-egy for breast cancer progression and metastasis treatment. Copyright (C) 2021, Chongqing Medical University. Production and hosting by Elsevier B.V.

Automated summary

This study reveals that overexpression of SQSTM1/p62 in breast cancer is correlated with poor prognosis. Silencing SQSTM1/p62 expression inhibits breast cancer progression by regulating cell proliferation and reshaping the tumor microenvironment. This finding provides a novel molecular therapeutic strategy for breast cancer treatment.