Abstract
LATS1, the large tumor suppressor 1 gene, encodes for a serine/threonine kinase protein and is implicated in cell cycle progression. LATS1 is down-regulated in various human cancers, such as breast cancer, and astrocytoma. Point mutations in LATS1 were reported in human sarcomas. Additionally, loss of heterozygosity of LATS1 chromosomal region predisposes to breast, ovarian, and cervical tumors. In the current study, we investigated LATS1 genetic variations including single nucleotide polymorphisms (SNPs), in 28 Egyptian patients with either urinary bladder or colon cancers. The LATS1 gene was amplified and sequenced and the expression of LATS1 at the RNA level was assessed in 12 urinary bladder cancer samples. We report, the identification of a total of 29 variants including previously identified SNPs within LATS1 coding and non-coding sequences. A total of 18 variants were novel. Majority of the novel variants, 13, were mapped to intronic sequences and un-translated regions of the gene. Four of the five novel variants located in the coding region of the gene, represented missense mutations within the serine/threonine kinase catalytic domain. Interestingly, LATS1 RNA steady state levels was lost in urinary bladder cancerous tissue harboring four specific SNPs (16045 + 41736 + 34614 + 56177) positioned in the 5′UTR, intron 6, and two silent mutations within exon 4 and exon 8, respectively. This study identifies novel single-base-sequence alterations in the LATS1 gene. These newly identified variants could potentially be used as novel diagnostic or prognostic tools in cancer.
Highlights
The large tumor suppressor gene (LATS1), encodes for a serine/threonine protein kinase
large tumor suppressor 1 (LATS1) AMPLIFICATION AND SEQUENCING Peritumoral urinary bladder tissues, urinary bladder cancer tissues, peritumoral colon tissue and colon cancer tissues were collected from 28 patients suffering from urinary bladder cancer or colon cancer
THE EXPRESSION OF LATS1 GENE HARBORING DIFFERENT single nucleotide polymorphisms (SNPs)/VARIANTS To assess if the various SNPs/variants alter the expression of the LATS1 gene, we examined the RNA steady state levels of LATS1 in the different urinary bladder cancer tissues utilized in this study (Figure 2)
Summary
The large tumor suppressor gene (LATS1), encodes for a serine/threonine protein kinase. It was first identified in Drosophila melanogaster and later two mammalian homologs LATS1 and LATS2 were identified (Yabuta et al, 2000, 2007). LATS1 shares functional and structural similarities with LATS2. They are core components of the Hippo signaling pathway that promotes tissue growth and regulates cell proliferation. Mutations in the Hippo signaling pathway have been associated with tissue overgrowth and development of tumors. The activation of the Hippo signaling inhibits cell proliferation through activation of the mammalian Ste20-like serine/threonine kinases 1 and 2 (MST1/2) that phosphorylates LATS1/2. Phosphorylated LATS1 in turn activates selected oncogenes such as yes-associated protein (YAP) or its paralog, the transcriptional co-activator with
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