No abstract

Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C () as a frequently mutated gene and examined its role in DGA progression. We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C () was analyzed in DGA cell lines and in patient tumors. was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage ( = 0.023) and worse overall survival ( = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival.

The nucleolar protein PinX1 has been proposed to be a putative tumor suppressor due to its binding to and inhibition of the catalytic activity of telomerase, an enzyme that is highly expressed in most human cancers in which it counteracts telomere shortening-induced senescence to confer cancer cell immortalization. However, the role of PinX1 in telomere regulation, as well as in cancer, is still poorly understood. In this study, we showed that the PinX1 protein is constitutively expressed in various human cells regardless of their telomerase activity and malignant status. Most interestingly, we found that silencing PinX1 expression by a potent short hairpin RNA construct led to a robust telomere length shortening and growth inhibition in telomerase-positive but not in telomerase-negative human cancer cells. We further showed that silencing PinX1 significantly reduced the endogenous association of telomerase with the Pot1-containing telomeric protein complex, and therefore, could account for the phenotypic telomere shortening in the affected telomerasepositive cancer cells. Our results thus reveal a novel positive role for PinX1 in telomerase/telomere regulations and suggest that the constitutive expression of PinX1 attributes to telomere maintenance by telomerase and tumorigenicity in cancer cells. [Cancer Res 2009;69(1):75-83]

A harvest of at least 21 LNs may represent a superior threshold for radical total gastrectomy (RTG) and could yield a better prognosis. For patients undergoing RTG, the hTNM staging system may predict survival more accurately and discriminatively. However, a validation from a Western institution is warranted.

Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital anomalies in humans. The pathogenesis of nsCL/P involves both genetic and environmental factors. On the basis of linkage data suggesting that 14q21-24 is one of the chromosomal regions that affects nsCL/P and data locating the BMP4 gene to 14q22-23, we performed a case-control study to evaluate whether BMP4 538T/C polymorphism, resulting in an amino acid change of Val/Ala (V152A) in the polypeptide, is associated with nsCL/P in a Chinese children population. Genotypes of 184 patients with nsCL/P and 205 controls were detected using a PCR-RFLP strategy. The results showed significant differences in the genotype and allele distribution of 538T/C polymorphisms of the BMP4 gene among the cases and controls. The 538C allele carriers were associated with a significantly increased risk of nsCL/P as compared with the noncarriers (odds ratio = 1.52; 95% confidence interval, 1.13-2.03; p = 0.005). Hence, our results support the hypothesis that this polymorphism contributes to risk of nsCL/P, which suggests that BMP4 538T/C polymorphisms could be used as genetic susceptibility markers of nsCL/P.