The SNP rs560426 Within ABCA4-ARHGAP29 Locus and the Risk of Nonsyndromic Oral Clefts.

OBJECTIVE: Nonsyndromic oral clefts are common birth defect with complex etiology. In the present study, we attempt to further validate the possible role for ABCA4 and ARHGAP29 in the susceptibility to nonsyndromic oral clefts. DESIGN: We performed allelic transmission disequilibrium test analysis, on 10 eligible single nucleotide polymorphisms (SNPs) and SNP haplotypes using the Family-Based Association Test. PARTICIPANTS: The study sample consisted of 334 case-parent trios of nonsyndromic oral clefts from Taiwanese population, separated into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO) groups. RESULTS: We found only the SNP rs560426 within the ABCA4 gene showed strong association with NSCPO (P = .03498; Permuted P = .05382). No association between other 9 selected SNPs in ABCA4-ARHGAP29 region and the risk of nonsyndromic oral clefts was found. For the haplotype analyses, we found only haplotype T-C (rs570926 and rs3789431) in ABCA4 block 2 showed significant association with nonsyndromic NSCL/P in these Taiwanese trios. CONCLUSIONS: We used a family-based analysis in 334 Taiwanese case-parent trios to validate the possible role for ABCA4 and ARHGAP29 in the susceptibility to nonsyndromic oral clefts. This study provides a new evidence for an association between the intron variant rs560426 within ABCA4 and nonsyndromic cleft palate which may contribute their regulatory role in craniofacial development.

Association Studies Between Regulatory Regions of IRF6/TP63 Genes and Nonsyndromic Oral Clefts.

OBJECTIVE: To evaluate genetic variants within the regulatory regions of interferon regulatory factor 6 (IRF6) and TP63 for the etiology of nonsyndromic oral clefts risk factors. DESIGN: We performed allelic transmission disequilibrium test analysis on 5 eligible single-nucleotide polymorphisms (SNPs) and SNP haplotypes using the Family-Based Association Test. PARTICIPANTS: The study sample consisted of 334 case-parent trios of nonsyndromic oral clefts from Taiwanese population, separated into nonsyndromic cleft lip/palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO) groups. RESULTS: We found all 3 selected SNPs of the IRF6 gene show significant association with nonsyndromic oral clefts (rs2235371, P = 5.10E-07; rs642961, P = .00194; and rs77542756, P = 9.08E-07). Haplotype analyses identified 3 possible SNP combination haplotypes in the IRF6 gene and found that C-G-G showed significant undertransmission (P = .058), whereas 2 other haplotypes, T-G-A and C-A-G (P = 2.71E-06 and P = 5.00E-04, respectively), were significantly overtransmitted to the NSCL/P children but not to the NSCPO children. For the TP63 gene, we failed to detect evidence of nonsyndromic oral cleft association in the 2 SNPs within the TP63 large intron 1 region. CONCLUSIONS: We used a family-based analysis in 334 Taiwanese case-parent trios to evaluate selected SNPs of IRF6 genes and TP63 genes for a risk of orofacial clefting. This study provides additional evidence for an association between IRF6 and NSCL/P, including the genetic variants within the 5'-noncoding region of the gene. We also confirmed that NSCL/P and NSCPO individuals belong to different groups. For the TP63, our data did not favor the direct involvement of TAp63 isoforms during orofacial development.

ADAM9 enhances CDCP1 by inhibiting miR-1 through EGFR signaling activation in lung cancer metastasis.

MicroRNAs (miRNAs), which are endogenous short noncoding RNAs, can regulate genes involved in important biological and pathological functions. Therefore, dysregulation of miRNAs plays a critical role in cancer progression. However, whether the aberrant expression of miRNAs is regulated by oncogenes remains unclear. We previously demonstrated that a disintegrin and metalloprotease domain 9 (ADAM9) promotes lung metastasis by enhancing the expression of a pro-migratory protein, CUB domain containing protein 1 (CDCP1). In this study, we found that this process occurred via miR-1 down-regulation. miR-1 expression was down-regulated in lung tumors, but increased in ADAM9-knockdown lung cancer cells, and was negatively correlated with CDCP1 expression as well as the migration ability of lung cancer cells. Luciferase-based reporter assays showed that miR-1 directly bound to the 3'-untranslated region of CDCP1 and inhibited its translation. Treatment with a miR-1 inhibitor restored CDCP1 protein levels and enhanced tumor cell mobility. Overexpression of miR-1 decreased tumor metastases and increased the survival rate in mice. ADAM9 knockdown reduced EGFR signaling and increased miR-1 expression. These results revealed that ADAM9 down-regulates miR-1 via activating EGFR signaling pathways, which in turn enhances CDCP1 expression to promote lung cancer progression.