Erratum: PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer: Erratum.

[This corrects the article DOI: 10.7150/jca.66773.].

PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review.

PTPN2 (protein tyrosine phosphatase non-receptor 2), also called TCPTP (T cell protein tyrosine phosphatase), is a member of the PTP family signaling proteins. Phosphotyrosine-based signaling of this non-transmembrane protein is essential for regulating cell growth, development, differentiation, survival, and migration. In particular, PTPN2 received researchers' attention when Manguso et al. identified PTPN2 as a cancer immunotherapy target using in vivo CRISPR library screening. In this review, we attempt to summarize the important functions of PTPN2 in terms of its structural and functional properties, inflammatory reactions, immunomodulatory properties, and tumor immunity. PTPN2 exerts synergistic anti-inflammatory effects in various inflammatory cells and regulates the developmental differentiation of immune cells. The diversity of PTPN2 effects in different types of tumors makes it a potential target for tumor immunotherapy.

TIFA promotes colorectal cancer cell proliferation in an RSK- and PRAS40-dependent manner.

Previous studies have reported that TIFA plays different roles in various tumor types. However, the function of TIFA in colorectal cancer (CRC) remains unclear. Here, we showed that the expression of TIFA was markedly increased in CRC versus normal tissue, and positively correlated with CRC TNM stages. In agreement, we found that the CRC cell lines show increased TIFA expression levels versus normal control. The knockdown of TIFA inhibited cell proliferation but had no effect on cell apoptosis in vitro or in vivo. Moreover, the ectopic expression of TIFA enhanced cell proliferation ability in vitro and in vivo. In contrast, the expression of mutant TIFA (T9A, oligomerization site mutation; D6, TRAF6 binding site deletion) abolished TIFA-mediated cell proliferation enhancement. Exploration of the underlying mechanism revealed that the protein synthesis-associated kinase RSK and PRAS40 activation were responsible for TIFA-mediated CRC progression. In summary, these findings suggest that TIFA plays a role in mediating CRC progression. This could provide a promising target for CRC therapy.

PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer.

Breast cancer has become the most newly-diagnosed cancer and the 5th leading cause of cancer death worldwide. The 5-year survival rate of breast cancer is about 90%. However, the 5-year survival rate drops to <30% when metastasis to distant sites occurs. The blood vessel formation (i.e., angiogenesis) plays a crucial role during the metastatic process. In this study, we investigated the role of PFKFB4 in angiogenesis of breast cancer. Employing in vitro HUVEC tube formation or in vivo orthotopic mouse model, and gene editing or specific small inhibitors strategy, and utilizing qPCR, western blot, ELISA, or immunofluorescent/immunohistochemistry staining methods, we found the following: 1) PFKFB4 upregulates IL-6 expression via NF-κB signaling in breast cancer cells; 2) PFKFB4-induced lactate secretion contributes to NF-κB activation in breast cancer cells; 3) IL-6 elicits angiogenesis via STAT5A/P-STAT5 in HUVEC; 4) 5-MPN (a specific PFKFB4 inhibitor) suppresses angiogenesis in vitro and in vivo. Our findings suggest a potential strategy whereby 5-MPN may lead to an improved therapeutic outcome for breast cancer patients.

MCP-1 targeting: Shutting off an engine for tumor development.

A large amount of research has proven that monocyte chemotactic protein-1 (MCP-1) is associated with different types of disease, including autoimmune, metabolic and cardiovascular diseases. In addition, several studies have found that MCP-1 is associated with tumor development. MCP-1 expression level in the tumor microenvironment is associated with tumor development, including in tumor invasion and metastasis, angiogenesis, and immune cell infiltration. However, the precise mechanism involved is currently being investigated. MCP-1 exerts its effects mainly via the MCP-1/C-C motif chemokine receptor 2 axis and leads to the activation of classical signaling pathways, such as PI3K/Akt/mTOR, ERK/GSK-3ß/Snail, c-Raf/MEK/ERK and MAPK in different cells. The specific mechanism is still under debate; however, target therapy utilizing MCP-1 as a neutralizing antibody has been found to have a detrimental effect on tumor development. The aim of the present review was to examine the effect of MCP-1 on tumor development from several aspects, including its structure, its involvement in signaling pathways, the participating cells, and the therapeutic agents targeting MCP-1. The improved understanding into the structure of MCP-1 and the mechanism of action may facilitate new and practical therapeutic agents to achieve maximum performance in the treatment of patients with cancer.

Erratum: CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3ß/ß-catenin/OCT4 axis: Erratum.

[This corrects the article DOI: 10.7150/thno.51000.].

CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3ß/ß-catenin/OCT4 axis.

Rationale: Considerable evidence suggests that breast cancer metastasis and recurrence occur due to emergence of cancer stem cells (CSCs). In our previous study, we designed a high-throughput siRNA screening platform that identifies inflammation genes involved in the regulation of cancer cell stemness. We reported that CCL16 protein decreases OCT4 expression and reduces the ALDH+ subpopulation. However, the mechanism by which CCL16 maintains stem cell-like properties remains unclear. Methods: Tissue microarrays were used to evaluate CCL16 expression. Cancer stemness assays were performed in CCL16 knockdown and overexpressing cells in vitro and in a xenograft model in vivo. Human phosphokinase array, immunofluorescence and chromatin immunoprecipitation assays were performed to explore the underlying mechanism. Results: We report that CCL16 was overexpressed in breast tumors and significantly correlated with clinical progression. We found that silencing CCL16 in MDA-MB-231 and BT549 cells diminished CSC properties including ALDH+ subpopulation, side population, chemo-resistance, and sphere formation. Furthermore, mice bearing CCL16-silenced MDA-MB-231 xenografts had lower tumorigenic frequency and developed smaller tumors. Exploration of the underlying mechanism found that CCL16 selects CCR2 to activate p-AKT/GSK3ß signaling and facilitate ß-catenin nuclear translocation. Further, CCL16 binds to the OCT4 promoter and promotes OCT4 expression. In addition, shRNAs targeting CCR2 and XAV939 targeting ß-catenin abolished CCL16-mediated cancer stemness. Upstream, IL10 mediates STAT3 activation, which binds to the CCL16 promoter and enhances its expression. The STAT3-targeted inhibitor Stattic suppressed CCL16 expression in vitro and restrained tumor progression in vivo. Conclusions: We identified a potential CSC regulator and suggest a novel mechanism for how CCL16 governs cancer cell stemness. We propose that CCL16 could be an effective target for breast cancer therapy.