KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition

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.

Comprehensive genomic profile of cholangiocarcinomas in China

“…TMB-H was found to be associated with the response rate, PFS and overall survival of patients with cancer (71). KMT2C, AXIN2 and MAGI1 mutations were also reported to be associated with poor prognosis (72)(73)(74). These reports support the association between TMB and the mutations of KMT2C, AXIN2 and MAGI1.…”

α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

“…Nicotine and its derivatives such as NNK and NNN, can not only activate nAChRs, studies have also shown that lung cancers synthesize acetylcholine (ACh) and cytokines, which acted as autocrine growth factors that stimulate nAChRs in lung cancer despite a lack of exogenous nicotine . EMT is a key initiating event in the metastatic cascades of various cancers . The molecular mechanism of α5‐nAChR in lung cancer EMT is far from clear.…”

“…41,42 EMT is a key initiating event in the metastatic cascades of various cancers. [43][44][45] The molecular mechanism of α5-nAChR in lung cancer EMT is far from clear. In this study, we showed that the expression of α5-nAChR mediates Stat3/Jab1 signalling and promotes EMT by up-regulating N-cadherin and Vimentin expression.…”

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“…In addition, targeted inactivation of MLL3 in mice leads to epithelial tumor formation. MLL3 has been associated with decreased OS in patients with diverse tumor types [23,24]. In our patient group with metastatic cancer, TP53 and MLL3 were not associated with prognosis, possibly because of the increasing complexity of mechanisms of cancer evolution in metastatic compared to non-metastatic disease.…”