The Human ApoE4 Variant Reduces Functional Recovery and Neuronal Sprouting After Incomplete Spinal Cord Injury in Male Mice.

Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two apolipoprotein E (ApoE)4 alleles show worse functional outcomes and longer hospital stays after SCI, but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.

Myokines in skeletal muscle physiology and metabolism: Recent advances and future perspectives.

Myokines are molecules produced and secreted by skeletal muscle to act in an auto-, para- and endocrine manner to alter physiological function of target tissues. The growing number of effects of myokines on metabolism of distant tissues provides a compelling case for crosstalk between skeletal muscle and other tissues and organs to regulate metabolic homoeostasis. In this review, we summarize and discuss the current knowledge regarding the impact on metabolism of several canonical and recently identified myokines. We focus specifically on myostatin, ß-aminoisobutyric acid, interleukin-15, meteorin-like and myonectin, and discuss how these myokines are induced and regulated as well as their overall function. We also review how these myokines may serve as potential prognostic biomarkers that reflect whole-body metabolism and how they may be attractive therapeutic targets for treating muscle and metabolic diseases.

Elucidating the Role of Apolipoprotein E Isoforms in Spinal Cord Injury-Associated Neuropathology.

Spinal cord injury (SCI) is a devastating, life-altering, neurological event that affects ∼300,000 individuals in the United States. Currently, there are no effective treatments to reverse the neurological impairments caused by the lesion. Until a cure is available, there is an urgent need for strategies that can either spare injured neurons or promote neuroplasticity and functional recovery. Genetic links to outcomes after SCI may provide insights into the pathological mechanisms, and possible new avenues for drug development. In the present review, we discuss the current knowledge linking apolipoprotein E genotypes with better or worse functional outcomes after an SCI, and the possible molecular mechanisms that may contribute to this association.

MicroRNA-4719 and microRNA-6756-5p Correlate with Castration-Resistant Prostate Cancer Progression through Interleukin-24 Regulation.

Prostate cancer (PCa) is the second leading cause of cancer death in the United States. The five-year survival rate for men diagnosed with localized PCa is nearly 100%, yet for those diagnosed with aggressive PCa, it is less than 30%. The pleiotropic cytokine Interleukin-24 (IL-24) has been shown to specifically kill PCa cells compared to normal cells when overexpressed in both in vitro and in vivo studies. Despite this, the mechanisms regulating IL-24 in PCa are not well understood. Since specific microRNAs (miRNAs) are dysregulated in PCa, we used miRNA target prediction algorithm tools to identify miR-4719 and miR-6556-5p as putative regulators of IL-24. This study elucidates the expression profile and role of miR-4719 and miR-6756-5p as regulators of IL-24 in PCa. qRT-PCR analysis shows miR-4719 and miR-6756-5p overexpression significantly decreases the expression of IL-24 in PCa cells compared to the negative control. Compared to the indolent PCa and normal prostate epithelial cells, miR-4719 and miR-6756-5p are significantly overexpressed in castration-resistant prostate cancer (CRPC) cell lines, indicating that their gain may be an early event in PCa progression. Moreover, miR-4719 and miR-6756-5p are significantly overexpressed in the CRPC cell line of African-American males (E006AA-hT) compared to CRPC cell lines of Caucasian males (PC-3 and DU-145), indicating that miR-4719 and miR-6756-5p may also play a role in racial disparity. Lastly, the inhibition of expression of miR-4719 and miR-6756-5p significantly increases IL-24 expression and inhibits proliferation and migration of CRPC cell lines. Our findings indicate that miR-4719 and miR-6756-5p may regulate CRPC progression through the targeting of IL-24 expression and may be biomarkers that differentiate between indolent and CRPC. Strategies to inhibit miR-4719 and miR-6756-5p expression to increase IL-24 in PCa may have therapeutic efficacy in aggressive PCa.

A novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in prostate cancer.

Prostate cancer (PCa) is the second most common cause of cancer-specific deaths in the U.S. Unfortunately, the underlying molecular mechanisms for its development and progression remain unclear. Studies have established that microRNAs (miRNAs) are dysregulated in PCa. The intron-derived microRNA-1207-3p (miR-1207-3p) is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, miR-1207-3p in PCa had not previously been investigated. Therefore, we explored if miR-1207-3p plays any regulatory role in PCa. We discovered that miR-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells, and that increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of fibronectin type III domain containing 1 (FNDC1). Our studies also revealed significant overexpression of FNDC1, fibronectin (FN1) and the androgen receptor (AR) in human PCa cell lines as well as tissues, and FNDC1, FN1, and AR positively correlate with aggressive PCa. These findings, recently published in Experimental Cell Research, are the first to describe a novel miR-1207-3p/FNDC1/FN1/AR novel regulatory pathway in PCa.

Fibronectin and androgen receptor expression data in prostate cancer obtained from a RNA-sequencing bioinformatics analysis.

Prostate cancer is the second most commonly diagnosed male cancer in the world. The molecular mechanisms underlying its development and progression are still unclear. Here we show analysis of a prostate cancer RNA-sequencing dataset that was originally generated by Ren et al. [3] from the prostate tumor and adjacent normal tissues of 14 patients. The data presented here was analyzed using our RNA-sequencing bioinformatics analysis pipeline implemented on the bioinformatics web platform, Galaxy. The relative expression of fibronectin (FN1) and the androgen receptor (AR) were calculated in fragments per kilobase of transcript per million mapped reads, and represented in FPKM unit. A subanalysis is also shown for data from three patients, that includes the relative expression of FN1 and AR and their fold change. For interpretation and discussion, please refer to the article, "miR-1207-3p regulates the androgen receptor in prostate cancer via FNDC1/fibronectin" [1] by Das et al.

miR-1207-3p regulates the androgen receptor in prostate cancer via FNDC1/fibronectin.

Prostate cancer (PCa) is frequently diagnosed in men, and dysregulation of microRNAs is characteristic of many cancers. MicroRNA-1207-3p is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of microRNA-1207-3p in PCa is unclear. We discovered that microRNA-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells. Increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of FNDC1, a protein which contains a conserved protein domain of fibronectin (FN1). FNDC1, FN1, and the androgen receptor (AR) are significantly overexpressed in PCa cell lines and human PCa, and positively correlate with aggressive PCa. Prostate tumor FN1 expression in patients that experienced PCa-specific death is significantly higher than in patients that remained alive. Furthermore, FNDC1, FN1 and AR are concomitantly overexpressed in metastatic PCa. Consequently, these studies have revealed a novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in PCa.

miR-1207-3p Is a Novel Prognostic Biomarker of Prostate Cancer.

MicroRNAs (miRNAs) have been found to be dysregulated in prostate cancer (PCa). In this study, we investigated if miR-1207-3p is capable of distinguishing between indolent and aggressive PCa and if it contributes to explaining the disproportionate aggressiveness of PCa in men of African ancestry (moAA). A total of 404 patients with primary adenocarcinoma of the prostate were recruited between 1988 and 2003 at the Moffitt Cancer Center, Tampa, FL, USA. Patient clinicopathological features and demographic characteristics such as race were identified. RNA samples from 404 postprostatectomy prostate tumor tissue samples were analyzed by real-time quantitative reverse transcription polymerase chain reaction for the mRNA expression of miR-1207-3p. miR-1207-3p expression in PCa that resulted in overall death or PCa-specific death is significantly higher than in PCa cases that did not. The same positive correlation holds true for other clinical characteristics such as biochemical recurrence, Gleason score, clinical stage, and prostate-specific antigen level. Furthermore, miR-1207-3p expression was significantly less in moAA in comparison to Caucasian men. We also evaluated whether miR-1207-3p is associated with clinical outcomes adjusted for age at diagnosis and tumor stage in the modeling. Using competing risk regression, the PCa patients with a high miR-1207-3p expression (≥6 vs 3) had a high risk to develop PCa recurrence (hazard rate = 2.5, P < .001) adjusting for age at diagnosis and tumor stage. In conclusion, miR-1207-3p is a promising novel prognostic biomarker for PCa. Furthermore, miR-1207-3p may also be important in explaining the disproportionate aggressiveness of PCa in moAA.

A "Patient-Like" Orthotopic Syngeneic Mouse Model of Hepatocellular Carcinoma Metastasis.

The majority of cancer-related deaths are caused by the metastasis of the cancer rather than the primary tumor itself. Yet, the underlying mechanisms of cancer metastasis are still unclear. Animal models are essential for elucidating the mechanisms and for evaluating novel strategies for the treatment of metastatic cancers. Here, an in-depth description of a "patient-like" orthotopic syngeneic mouse model for exploring the mechanisms of metastasis of solid organ tumors is provided. The survival surgical implantation of BNL 1ME A.7R.1 mouse hepatocellular carcinoma cells directly into the liver (the organ of origin) of the inbred wild-type immune competent laboratory mouse strain, BALB/c is described. The success and reproducibility of this methodology recommends it for widespread use in elucidating the biological mechanisms of solid organ cancer metastasis.

Isolation and Propagation of Circulating Tumor Cells from a Mouse Cancer Model.

Cancer metastasis is the foremost cause of cancer-associated deaths. Recent studies have shown that circulating tumor cells (CTCs) are important in cancer metastasis. Indeed, the number of CTCs correlates with tumor size. Here, a detailed description is provided of a methodology for isolation and propagation of CTCs from a syngeneic mouse model of hepatocellular carcinoma (HCC) which allows for downstream analysis of potentially important molecular mechanisms of solid organ tumor metastasis. This method is efficient and reproducible. It is a non-invasive technique and, therefore, has potential to replace the invasive biopsy of tissues from humans which may be associated with complications. Therefore, the method discussed here allows for the isolation and propagation of CTCs from whole blood samples such that they can be examined and characterized. This has potential for future adaptation for clinical applications such as diagnosis, and personalized targeted therapy.