Methylation silencing of ULK2 via epithelial–mesenchymal transition causes transformation to poorly differentiated gastric cancers

2021 ◽  
Author(s):  
Iori Motoo ◽  
Sohachi Nanjo ◽  
Takayuki Ando ◽  
Satoshi Yamashita ◽  
Toshikazu Ushijima ◽  
...  
Pathobiology ◽  
2018 ◽  
Vol 85 (4) ◽  
pp. 232-246 ◽  
Author(s):  
Yoshifumi Takei ◽  
Guodong Shen ◽  
Ayami Morita-Kondo ◽  
Toshifumi Hara ◽  
Keichiro Mihara ◽  
...  

Gut ◽  
2018 ◽  
Vol 68 (7) ◽  
pp. 1245-1258 ◽  
Author(s):  
Wenjia Wang ◽  
Scott C Friedland ◽  
Bing Guo ◽  
Michael R O’Dell ◽  
William B Alexander ◽  
...  

ObjectiveHere, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (ARID1A), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models.DesignMice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes.ResultsArid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a, leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation.ConclusionsARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.


2019 ◽  
Vol 20 (3) ◽  
pp. 555 ◽  
Author(s):  
Jung Jo ◽  
Soo Park ◽  
Semi Park ◽  
Hee Lee ◽  
Chanyang Kim ◽  
...  

The expression of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) has been reported in Parkinson’s disease; however, its role in other diseases is unknown. Gastric cancer is the second leading cause of cancer death. Cancer stem cells (CSC) are a subpopulation of cancer cells that contribute to the initiation and invasion of cancer. We identified LINGO2 as a CSC-associated protein in gastric cancers both in vitro and in patient-derived tissues. We studied the effect of LINGO2 on cell motility, stemness, tumorigenicity, and angiogenic capacity using cells sorted based on LINGO2 expression and LINGO2-silenced cells. Tissue microarray analysis showed that LINGO2 expression was significantly elevated in advanced gastric cancers. The overall survival of patients expressing high LINGO2 was significantly shorter than that of patients with low LINGO2. Cells expressing high LINGO2 showed elevated cell motility, angiogenic capacity, and tumorigenicity, while LINGO2 silencing reversed these properties. Silencing LINGO2 reduced kinase B (AKT)/extracellular signal-regulated kinase (ERK)/ERK kinase (MEK) phosphorylation and decreased epithelial-mesenchymal transition (EMT)-associated markers—N-Cadherin and Vimentin and stemness-associated markers— POU class 5 homeobox 1 (OCT4) and Indian hedgehog (IHH), and markedly decreased the CD44+ population. These indicate the involvement of LINGO2 in gastric cancer initiation and progression by altering cell motility, stemness, and tumorigenicity, suggesting LINGO2 as a putative target for gastric cancer treatment.


2018 ◽  
Vol 69 (10) ◽  
pp. 2638-2641 ◽  
Author(s):  
Simina Boia ◽  
Eugen Radu Boia ◽  
Raluca Amalia Ceausu ◽  
Constantin Nicolae Balica ◽  
Ovidiu Alexandru Mederle

HPV is an important oropharyngeal cancer cause, but it may have a role in other head and neck cancers? HPVpositive head and neck squamous cell carcinoma (HNSCC) epithelial-mesenchymal transition role is unclear. We included 38 cases: 20 laryngeal, 3 corresponding lymph nodes; 5 oropharyngeal, 5 hypopharyngeal, 2 rhynopahryngeal, 2 pharyngolaryngeal and 1 naso-sinusal case. Immunoreactivity was positive in nuclear expression cells, accordingly: score 1 (10-30%), 2 (30-50%) and 3 (]50%). HPV18 immunoexpression appeared in 18 cases (47.36%), (11 laryngeal, 4 oropharyngeal, 1 hypopharyngeal, 1 pharyngolaryngeal and 1 naso-sinusal). The score was 1 in larynx well differentiated type. The score was between 1 and 3 in larynx moderately differentiated types, and a significant correlation HPV18/E-cadherin was found (p=0.031). HPV18+/E-cadherin low values were noticed in larynx, oropharynx, pharyngo-larynx and naso-sinusal well and moderately differentiated types. HPV18-/E-cadherin low values were present in larynx, hypo and rhyno-pharynx moderately and poorly differentiated and larynx well differentiated types. Larynx presented HPV18/E-cadherin and moderately differentiated type significant correlation. Rhyno, hypo-pharyngeal and laryngeal presented HPV18�/E-cadherin low values association for moderately, poorly and undifferentiated types. The oropharyngeal location was associated with E-cadherin maximum values, independently of HPV18 status.


2018 ◽  
Vol 19 (8) ◽  
pp. 2411 ◽  
Author(s):  
Armando Cevenini ◽  
Stefania Orrù ◽  
Annamaria Mancini ◽  
Andreina Alfieri ◽  
Pasqualina Buono ◽  
...  

The insulin-like growth factor (IGF) system, which is constituted by the IGF-1 and IGF-2 peptide hormones, their corresponding receptors and several IGF binding proteins, is involved in physiological and pathophysiological processes. The IGF system promotes cancer proliferation/survival and its signaling induces the epithelial-mesenchymal transition (EMT) phenotype, which contributes to the migration, invasiveness, and metastasis of epithelial tumors. These cancers share two major IGF-1R signaling transduction pathways, PI3K/AKT and RAS/MEK/ERK. However, as far as we could review at this time, each type of cancer cell undergoes EMT through tumor-specific routes. Here, we review the tumor-specific molecular signatures of IGF-1-mediated EMT in breast, lung, and gastric cancers.


Author(s):  
Kosuke Saku ◽  
Nobuhiro Tahara ◽  
Yoshihiro Fukumoto ◽  
Hiroyuki Tanaka

Abstract Background Hepatocellular carcinoma (HCC) that metastasizes to the right ventricle has rarely been reported. An important link between epithelial–mesenchymal transition (EMT) and the invasion and metastasis of cancer cells has recently been demonstrated. However, there are few reports on the relationship between HCC metastasized to the heart and EMT. Case summary We here report the case of a 74-year-old woman who had type C HCC referred to our hospital with general fatigue due to a right ventricular tumour diagnosed at a general hospital. Anticoagulation therapy was done, but the mass had rapidly grown. We performed surgical resection of the mass. Histopathological examination revealed that the tumour was diagnosed as a poorly differentiated HCC metastasis induced by EMT. Discussion Isolated metastasis of HCC to the right ventricle is extremely rare. The HCC with EMT has a potentially high risk of metastasizing to the heart and other organs, and the prognosis is poor.


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