Ilyas, M. | Search bioRxiv

bioRxiv2018

TGFβ1-induced cell motility is mediated through Cten in colorectal cancer

Cten is a tensin which promotes epithelial-mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although Cten could be regulated by several cytokines and growth factors. Since Transforming growth factor beta 1 (TGF-{beta}1) regulates integrin function and promotes EMT / cell motility, we investigated whether this happens through Cten signalling in colorectal cancer (CRC).\n\nTGF-{beta}1 signalling was modulated by either stimulation or knockdown in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and cellular function was tested. Cten role as a direct mediator of TGF-{beta}1 signalling was investigated in a CRC cell line with a deleted Cten gene (SW620{Delta}Cten).\n\nWhen TGF-{beta}1 was stimulated or inhibited, this resulted in, respectively, upregulation and downregulation of Cten expression and EMT markers. Cell migration and invasion were significantly increased following TGF-{beta}1 stimulation and lost by TGF-{beta}1 knockdown. TGF-{beta}1 stimulation in SW620{Delta}Cten resulted in selective loss of the effect of TGF-{beta}1 signalling on EMT and cell motility whilst the stimulatory effect on cell proliferation was retained.\n\nThese data suggested Cten may play an essential role in mediating TGF-{beta}1-induced EMT and cell motility and may play a role in metastasis in CRC.

cancer biology↗

bioRxiv2016

Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7, and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

genetics↗