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 expression 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 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 SQSTM1/p62 suppressed tumor cell lung metastasis. Together, our results provide strong evidence 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 strategy for breast cancer progression and metastasis treatment.

自噬衔接蛋白 SQSTM1/p62 在乳腺癌中过度表达，已被确定为转移相关蛋白。然而，SQSTM1/p62 促进乳腺癌进展和肿瘤微环境的机制仍不清楚。这项研究表明，沉默SQSTM1/p62表达通过调节细胞增殖和重塑肿瘤微环境 (TME) 来抑制乳腺癌的进展。在这里，我们发现 SQSTM1/ p 62 在多种人类癌症组织类型中过表达，这与患者总生存期 (OS) 和无病生存期 (DFS) 较差相关。此外，我们发现短发夹 RNA (shRNA) 介导的p62敲低表达显着抑制细胞增殖、迁移和侵袭，并在体外促进细胞死亡，并在体内抑制乳腺癌生长和肺转移。此外，脾细胞和肿瘤浸润淋巴细胞（TILs）的流式细胞术分析表明，CD8α ⁺干扰素（IFN）-γ ⁺细胞（CTLs）和CD4 ⁺ IFN-γ ⁺（Th1）细胞的数量增加，而CD4 ⁺ IL-4 ⁺(Th2) 细胞、肿瘤相关巨噬细胞 (TAM) 和髓源性抑制细胞 (MDSC) 减少。RT-PCR分析表明，Th1/Th2细胞因子的基因表达在肿瘤微环境中发生了变化。沉默SQSTM1 / p 62 抑制了肿瘤细胞肺转移。总之，我们的结果提供了强有力的证据，即沉默肿瘤细胞SQSTM1 / p 62 通过细胞周期停滞和 TME 调节抑制肿瘤生长和转移。这一发现为乳腺癌进展和转移治疗提供了一种新的分子治疗策略。