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

Abstract

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 <i>SQSTM1/p62</i> expression suppressed breast cancer progression via regulating cell proliferation and reshaping the tumor microenvironment (TME). Here, we found that SQSTM1/<i>p</i>62 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 <i>p62</i> expression significantly inhibited cell proliferation, migration, and invasion, and promoted cell death <i>in vitro</i>, as well as suppressed breast cancer growth and lung metastasis <i>in vivo</i>. In addition, flow cytometry analysis of splenocytes and tumor infiltrating lymphocytes (TILs) indicated that the numbers of CD8α⁺ interferon (IFN)-γ⁺ cells (CTLs) and CD4⁺IFN-γ⁺ (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 <i>SQSTM1</i>/<i>p</i>62 suppressed tumor cell lung metastasis. Together, our results provide strong evidence that silencing tumor cell <i>SQSTM1</i>/<i>p</i>62 inhibited tumor growth and metastasis through cell cycle arrest and TME regulation. This finding provides a novel molecular therapeutic strategy for breast cancer progression and metastasis treatment.