Semaphorin 4D promotes bone invasion in head and neck squamous cell carcinoma

Head and neck squamous cell carcinomas (HNSCCs) frequently invade the bones of the facial skeleton. Semaphorin 4D (Sema4D) is an axon guidance molecule produced by oligodendrocytes. Sema4D was also identified in the bone microenvironment and many cancer tissues including HNSCC. To date, however, the role of Sema4D in cancer-associated bone disease is still unknown. This is the first study to demonstrate the role of Sema4D in bone invasion of cancer. In the clinical tissue samples of bone lesion of HNSCC, Sema4D was detected at high levels, and its expression was correlated with insulin-like growth factor-I (IGF-I) expression. In vitro experiments showed that IGF-I regulates Sema4D expression and Sema4D increased proliferation, migration and invasion in HNSCC cells. Sema4D also regulated the expression of receptor activator of nuclear factor κβ ligand (RANKL) in osteoblasts, and this stimulated osteoclastgenesis. Furthermore, knockdown of Sema4D in HNSCC cells inhibited tumor growth and decreased the number of osteoclasts in a mouse xenograft model. Taken together, IGF-I-driven production of Sema4D in HNSCCs promotes osteoclastogenesis and bone invasion

MiR-145 expression and rare NOTCH1 variants in bicuspid aortic valve-associated aortopathy

<div><p>MicroRNAs (miRNAs) may serve as elegant tool to improve risk stratification in bicuspid aortic valve (BAV)-associated aortopathy. However, the exact pathogenetic pathway by which miRNAs impact aortopathy progression is unknown. Herewith, we aimed to analyze the association between circulating miRNAs and rare variants of aortopathy-related genes. 63 BAV patients (mean age 47.3±11.3 years, 92% male) with a root dilatation phenotype, who underwent aortic valve+/-proximal aortic surgery at a single institution (mean post-AVR follow-up 10.3±6.9 years) were analyzed. A custom-made HaloPlex HS panel including 20 aortopathy-related genes was used for the genetic testing. miRNAs were extracted from whole blood and miRNA analysis was performed using miRNA-specific assay. Study endpoint was the association between circulating miRNAs and rare genetic variants in the aortopathy gene panel. The study cohort was divided into a subgroup with rare variants vs. a subgroup without rare variants based on the presence of rare variants in the respective genes (i.e., at least one variant present). The genetic analysis yielded n = 6 potentially and likely pathogenic rare variants within the <i>NOTCH1</i> gene as being the most common finding. Univariate analysis between blood miRNAs and <i>NOTCH1</i> variants revealed a significantly lower expression of miR-145 in the subgroup of patients with <i>NOTCH1</i> variants vs. those without <i>NOTCH1</i> variants (i.e., delta Ct 4.95±0.74 vs. delta Ct 5.57±0.78, p = 0.04). Our preliminary data demonstrate a significant association between blood miR-145 expression and the presence of rare <i>NOTCH1</i> variants. This association may be indicative of a specific pathogenetic pathway in the development of genetically-triggered bicuspid aortopathy.</p></div

Expression of miR-145 in patients with and without rare <i>NOTCH1</i> variants.

<p>Expression of miR-145 in patients with and without rare <i>NOTCH1</i> variants.</p

Correlation of individual microRNAs.

<p>Correlation of individual microRNAs.</p

Demographics and intraoperative variables.

<p>Demographics and intraoperative variables.</p

Rare genetic variants within the 20 candidate genes in the aortopathy gene panel [13].

<p>Rare genetic variants within the 20 candidate genes in the aortopathy gene panel [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200205#pone.0200205.ref013" target="_blank">13</a>].</p

Expression of microRNAs in patients with and without potentially/likely pathogenic NOTCH1 variants.

<p>Normalized delta Ct values are shown.</p

Potential mechanistic linkage between NOTCH1 variants, miR-145 expression and bicuspid aortopathy.

<p>Potential mechanistic linkage between NOTCH1 variants, miR-145 expression and bicuspid aortopathy.</p

Cox proportional hazard regression in the stable angina cohort (N = 2652).

<p>Stable Angina (N = 2652).</p

Cox Proportional Hazard Regression in the overall cohort (N = 3229).

<p>Overall Cohort (N = 3229).</p