Volume 01 · Issue 02 · 2018

Breast cancer metastasis is the root cause of deaths from breast cancer. Currently, endocrine therapy resistance in estrogen receptor (ER)-positive (ER⁺) breast cancer remains a major clinical issue. Moreover, ER-negative (ER^－) breast cancer is often associated with distant recurrence and death. G-protein-coupled ER (GPER1) participates in endocrine therapy resistance and is involved in the malignant progression of breast cancer. However, the underlying detailed mechanisms remain obscure. Here we investigated the role and mechanism of GPER1 in the activation of focal adhesion kinase (FAK) using ER⁺ or ER^－ breast cancer cell lines. In SK-Br-3 cells (ERα^－/β^－/GPER1 ⁺), both 17β-estradiol (E2) and the GPER1 agonist G1 resulted in rapid FAK phosphorylation. This action is due to GPER1 interaction with the non-receptor tyrosine kinase c-Src and subsequent activation of nuclear factor kappa B (NF-κB) signaling. Silencing of GPER1, c-Src or the nuclear factor kappa B p65 subunit blocked E2- or G1-induced SK-Br-3 cell migration and invasion. In MCF-7 cells (ERα⁺/β⁺/GPER1⁺), silencing of GPER1, but not ERα or ERβ, abolished FAK phosphorylation induced by E2 or G1. In MDA-MB-231 cells (ERα^－/β⁺/GPER1^－), E2 or G1 was also unable to stimulate E2-induced FAK phosphorylation. However, E2 and G1 regained the ability to induce FAK phosphorylation under conditions of overexpression of GPER1. In conclusion, we demonstrated that GPER1, but not ERα or ERβ, mediates FAK phosphorylation induced by E2 via the c-Src/p65 signaling pathway, which enhances cell migration and invasion. These findings may shed light on novel therapeutic strategies based on GPER1/FAK signaling pathways in suppression of breast cancer metastasis.

Metastasis is the main cause of cancer-specific death in patients with prostate cancer (PCa). Acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) is involved in the metabolic reprogramming of multiple types of cancer cells, but its role in PCa metastasis remains largely unknown. Here, we determined the effect of overexpression or small interfering RNA-mediated depletion of ACSL3 on the migratory and invasive abilities of human PCa cell lines. We also conducted phospho-protein microarray analysis to identify signaling pathway components affected by ACSL3 modulation. Overexpression of ACSL3 promoted the migration and invasion of PCa cells, whereas ACSL3 downregulation had the opposite effects. Mechanistically, phospho-protein analysis showed that ACSL3 regulated the phosphorylation of AKT and the expression of matrix metalloproteinase9. Our results support a potential role for ACSL3 in promoting the metastatic behavior of PCa, possibly via AKT/matrix metalloproteinase9 pathways. Thus, ACSL3 could be a novel target for the development of treatments for PCa.

Phosphatase of regenerating liver 3 (PRL3) promotes colorectal cancer (CRC) metastasis by inducing epithelial-to-mesenchymal transition. Mesenchymal-to-epithelial transition (MET), the opposite of epithelial-to-mesenchymal transition, has been proposed as a mechanism for the establishment of metastatic neoplasms. However, the molecular mechanism of MET remains unclear. Here, we show that miR-203a-3p derived from hepatocyte exosomes inhibits Src expression, reduces epidermal growth factor receptor activity and downstream signaling pathways, and increases E-cadherin expression, which is a typical mesenchymal cell marker of MET, in CRC cells. These results show the important role of epidermal growth factor receptor in CRC cell MET.

The majority of patients who experience cutaneous adverse drug reactions (cADRs) concurrently receive multiple medications, meaning that the causative drug remains unidentified. We explored the association between human leukocyte antigen (HLA) alleles and cADRs, regardless of the allergenic drug, to investigate whether different drug-induced cADRs were associated with the same or similar risk alleles in a Han Chinese population. We genotyped a sample of 146 cADR patients and 230 population controls from the same hospital and systematically analyzed the association between HLA Class I genes and cADRs. The carrier frequency of HLA-B*46:01 in cADR patients was found to be significantly higher than that in population controls (P= .0021, odds ratio [OR] = 2.18, 95% confidence interval [CI]: 1.33–2.58). Subgroup analysis showed that HLA-B*46:01 was significantly associated with urticaria and erythema multiforme (P=.0077, OR= 2.53, 95% CI: 1.30–4.91; and P=.0049, OR= 2.77, 95% CI: 1.39–5.50, respectively). Furthermore, a significant association was also detected between HLA-A*02:01 and erythema multiforme (P=.0038, OR= 2.65, 95% CI: 1.31–5.33). This study is the first to demonstrate that HLA-B*46:01 is a risk allele for cADRs in a Han Chinese population, indicating that screening for HLA-B*46:01 prior to the administration of medication may predict the risk of developing cADRs.

Human immunodeficiency virus (HIV)-infected individuals exhibit remarkable transcriptomic variation. Transcriptome analyses of antiretroviral therapy (ART)-free chronically infected HIV-1 patients with different clinical outcomes are likely to aid the development of vaccine and immune therapies. Here, we performed microarray analyses on whole-blood derived RNA from 89 ART-free HIV-1-infected individuals from 2 cohorts. The differentially expressed genes were analyzed between long-term non-progressors, viremic non-progressors and typical progressors, and between elite controllers and non-elite controllers among the long-term non-progressors. Several genes related to T-cell growth, proliferation and differentiation and antiapoptosis were upregulated, whereas interferon-stimulated genes and inflammatory genes were significantly downregulated in long-term non-progressors and viremic non-progressors. The observations above were further confirmed in the set of 261 genes that correlated with disease progression during a 5-year follow-up, which included 51 genes significantly associated with slower disease progression, and 210 genes associated with aggressive disease progression. Overall, our data suggest that it is vital to maintain the homeostasis of the immune system when mounting antiviral immune responses. Immune therapeutics able to reconstruct immune homeostasis are likely to be required for immune reconstitution in the context of ART, such as the administration of interleukin-7, healthy allogenic CD4⁺ T cells (providing CD4⁺ T-cell growth factors), or Tregs.

Male breast cancer accounts for less than 0.5%of all breast cancer, and Paget's disease of the breast in males is extremely rare. Here, we report 2 cases of Paget's disease of the nipple areola complex with invasive ductal carcinoma as typical examples of male PDB. Case 1 was a 64-year-old man with an altered appearance of the left nipple, itching and redness, without a palpable breast mass at first. Case 2 was a 55-year-old man with a palpable mass in the left breast and histologically confirmed Paget's disease of the nipple with invasive ductal carcinoma. Both patients underwent modified radical mastectomy but with different adjuvant therapies and remained well during follow-up with no recurrence. Furthermore, we reviewed all the sporadic cases of male PDB from the literature. This may help contribute to the development of diagnostic strategies and appropriate interventions for male Paget's disease of the breast.

This review aims to compile recent advances regarding the significance of Notch signaling in different types of intrahepatic cells during liver injury and repair. The functions of Notch signaling in regulating cell development, fate decisions, and organ homeostasis have been widely acknowledged. Notch is also expressed and activated in hepatocytes, macrophages, liver sinusoidal endothelial cells, endothelial progenitor cells, and hepatic progenitor cells during the process of development, injury, inflammation, fibrosis, and carcinoma. During acute/chronic liver injury, Notch interacts with many signaling pathways that are involved in liver repair. Recent research, including ours, has confirmed the crucial role of Notch signaling in modulating the function of diverse intrahepatic cells during liver injury and reconstruction. Thus, Notch signaling may serve as a potential therapeutic target for liver diseases.