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

Flow chart of the NFBC1966 data collections.

<p>Flow chart of the NFBC1966 data collections.</p

Estimated associations between variants in the 15q25 region and DBP by smoking status (non-smokers, smokers) in the NFBC1966.

a<p>Effect allele is the smoking-increasing allele (as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046557#pone.0046557-Ducci1" target="_blank">[15]</a>). Minor allele is in bold.</p>b<p>Linear regression model including SNP, gender, BMI at 31 years, three first PCs.</p>c<p>Interaction model including SNP, gender, BMI at 31 years, smoking (no,yes), three first PCs, SNP*smoking.</p>d<p>Adjustment for multiple testing by MaxT bootstrap test for gene-environment interaction.</p

Associations between the <i>CHRNA5-CHRNA3-CHRNB4</i> gene cluster on the three outcomes of interest.

<p>(A) Systolic blood pressure, non-smokers. (B) Systolic blood pressure, smokers. (C) Diastolic blood pressure, non-smokers. (D) Diastolic blood pressure, smokers. (E) Body mass index, non-smokers. (F) Body mass index, smokers. Blue diamond indicates the most statistically significantly associated SNP, and other SNPs in the region are presented by diamonds with coloring from white to red corresponding to r² values from 0 to 1. The SNP position refers to the NCBI build 35. Estimated recombination rates are from HapMap, and gene annotations from University of California at Santa Cruz genome browser with build 35 coordinates.</p

Estimated associations between variants in the 15q25 region and BMI by smoking status (non-smokers, smokers) in the NFBC1966.

a<p>Effect allele is the smoking-increasing allele (as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046557#pone.0046557-Ducci1" target="_blank">[15]</a>). Minor allele is in bold.</p>b<p>Linear regression model including SNP, gender, three first PCs.</p>c<p>Interaction model including SNP, gender, smoking (no, yes), three first PCs, SNP*smoking.</p>d<p>Adjustment for multiple testing by MaxT bootstrap test for gene-environment interaction.</p

Estimated associations between variants in the 15q25 region and SBP by smoking status (non-smokers, smokers) in the NFBC1966.

a<p>Effect allele is the smoking-increasing allele (as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046557#pone.0046557-Ducci1" target="_blank">[15]</a>). Minor allele is in bold.</p>b<p>Linear regression model including SNP, gender, BMI at 31 years, three first PCs.</p>c<p>Interaction model including SNP, gender, BMI at 31 years, smoking (no,yes), three first PCs, SNP*smoking.</p>d<p>Adjustment for multiple testing by MaxT bootstrap test for gene-environment interaction.</p

Sample characteristics of the NFBC1966 study sample.

<p>Sample characteristics of the NFBC1966 study sample.</p

Illustration of how the identified molecules are relevant within the DISC1 pathway.

<p>Illustration of how the identified molecules are relevant within the DISC1 pathway.</p

Flowchart of study participants.

<p>Flowchart of study participants.</p