Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking β2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.

Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gαi1/3) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gαi1/3 form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gαi1/3 deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gαi1/3 knockdown in bone marrow-derived macrophage cells (Gαi1/3 KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Gαi1/3 deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gαi1/3 were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gαi1/3 can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo.

Background: MicroRNAs (miRNAs) are a class of small non-coding RNAs (18-25 nucleotides) which post-transcriptionally regulate gene expression by negatively regulating the stability or translational efficiency of their target mRNAs. This study aimed to determine the function of miR-154-5p in prostate cancer (PCa) cells and identify the novel molecular targets regulated by miR-154-5p. Materials and Methods: The effects of forced miR-154-5p expression or E2F transcription factor 5 (E2F5) knockdown on PCa cells were evaluated by cell proliferation, flow cytometry, cell migration and invasion assays as well as by Western blot analysis. Dual-luciferase reporter assay was performed to verify the precise target of miR-154-5p. Results: The forced expression of miR-154-5p or E2F5 knockdown significantly restrained cell growth, as well as the migratory and invasive capabilities. Such expression also induced G₁ cell cycle arrest of PCa cells in vitro. Hence, E2F5 is a direct target gene of miR-154-5p. Conclusions: miR-154-5p may play an important role as an inhibitor of proliferation, migration and invasion of PCa by targeting E2F5 in PCa cell lines.

Bladder cancer (BC) is one of the most common cancers in the world, with high morbidity and mortality. It is essential to develop a non-invasive, highly accurate, and simple method for BC diagnosis. This work proposed a fluorescent biosensor based on inorganic nanoflares combined with a DNAzyme walker for the simultaneous detection of BC exosomal microRNAs (miRNAs). This biosensor was constructed on the Au nanoparticle (AuNP) modified with the carbon dot (CD)-labeled substrates and DNAzyme strands (AuNP@CDs inorganic nanoflares-DNAzyme, APCD). In the presence of target miRNAs, DNAzyme was activated and then cleaved the CD-labeled substrates and automatically walked along the AuNP, allowing fluorescence recovery. Due to the structure and functional composition, the APCD biosensors demonstrated high sensitivity and specificity, with the reached limit of detection for a single miRNA at the femtomolar level and wide linear range from 50 fM to 10 nM. Furthermore, the simultaneous analysis of BC-related exosomal miR-133b and miR-135b in clinical serum specimens was achieved and consistent with qRT-PCR, suggesting it is a potential method for the diagnosis of BC and other cancers.

Androgen receptor (AR) is a key transcription factor playing a critical role in prostate cancer (PCa) initiation and progression. However, the molecular mechanisms of AR action in prostate cancer are not very clear. CXCL13, known as B cell attracting chemokine1 (BCA-1), is a member of CXC chemokine family and relevant to cancer metastasis. This study shows that CXCL13 is an androgen-responsive gene and involved in AR-induced PCa cell migration and invasion. In clinical specimens, expression of CXCL13 in PCa tissues is markedly higher than that in adjacent normal tissues. In cultures, expression of CXCL13 is up-regulated by androgen-AR axis at both mRNA and protein levels. Furthermore, Chip-Seq assay identifies canonical androgen responsive elements (ARE) at CXCL13 enhancer and dual-luciferase reporter assays reveals that the ARE is highly responsive to androgen while mutations of the ARE abolish the reporter activity. Additional chromatin immunoprecipitation (ChIP) assays also identify that the ARE presents androgen responsiveness. In addition, CXCL13 promotes G2/M phase transition by increasing Cyclin B1 levels in PCa cells. Functional studies demonstrate that reducing endogenous CXCL13 expression in LNCaP cells largely weakens androgen-AR axis induced cell migration and invasion. Taken together, our study implicates for the first time that CXCL13 is an AR target gene and involved in AR-mediated cell migration and invasion in primary PCa.