Expression of protein tyrosine phosphatase alpha (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo

e15570 Background: We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human breast cancer (BC). Methods: The expression and correlation of all the indices were explored in monocytes and tumor infiltrating macrophages within both human and mice BC. The mechanic regulations were studied by using both in vitro and in vivo studies. Results: We found a significant decrease in PTPRO in BC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in BC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with BC and were associated with increased T cell exhaustion (Tim3+ T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25-3p axis. Monocytes and TAMs showed significantly increased miR-25-3p expression, which could target the 3' untranslated region of PTPRO. The miR-25-3p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in BC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25-3p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25-3p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in breast tumor model. Conclusions: Increased serum IL-6 downregulated PTPRO expression in BC monocytes and macrophages by activating STAT3/c-MYC/miR-25-3p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.

Download Full-text

Overexpression of PSMC2 promotes the tumorigenesis and development of human breast cancer via regulating plasminogen activator urokinase (PLAU)

Cell Death and Disease ◽

10.1038/s41419-021-03960-w ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Yanyan Wang ◽

Mingzhi Zhu ◽

Jingruo Li ◽

Youyi Xiong ◽

Jing Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Human Breast Cancer ◽

Tumor Grade ◽

Loss Of Function ◽

Human Breast ◽

Promising Therapeutic Target ◽

And Migration

AbstractEmerging evidence has declared that Proteasome 26S subunit ATPase 2 (PSMC2) is involved in tumor progression. However, its role in breast cancer has not been investigated. Therefore, we sought to establish a correlation between breast cancer and PSMC2. PSMC2 expression in tissues was detected by immunohistochemistry. Loss-of-function study was used to evaluate the effects of PSMC2 knockdown in cell proliferation, apoptosis and migration. A gene microarray was performed to explore the potential downstream of PSMC2 with the help of Ingenuity Pathway Analysis (IPA). The effects of the PSMC2/PLAU axis on breast cancer were examined in vitro. Compared to para-cancer tissues, PSMC2 level was considerably elevated in breast cancer, which was significantly correlated with tumor grade. Knockdown of PSMC2 suppressed breast cancer progression in vitro and in vivo. The mechanistic research revealed that PSMC2 promotes the development and progression of human breast cancer through interacting with PLAU. Outcomes of our study showed that overexpression of PSMC2 provide tumorigenic and metastatic advantages in breast cancer, which may involve the regulation of PLAU. This study not only reveals a critical mechanism of breast cancer development, but also provides a promising therapeutic target for breast cancer treatment.

Download Full-text