Elevated METTL9 is associated with peritoneal dissemination in human scirrhous gastric cancers

Methylation, the most common chemical modification of cellular components such as DNA, RNA, and proteins, impacts biological processes including transcription, RNA processing, and protein dynamics. Although abnormal expression of methyltransferase can lead to various diseases including cancers, little is known about the relationship between methyltransferase and cancers. Here we aimed to understand the role of methyltransferase in cancer metastasis. We found that elevated methyltransferase-like 9 (METTL9) is closely associated with the acquisition of metastatic activity in human scirrhous gastric cancers. The stable knockdown of METTL9 via an shRNA vector technique in our original metastatic cells from scirrhous gastric cancer patients significantly inhibited migration and invasion. In metastatic cells, METTL9 protein is predominantly localized in mitochondria, and the METTL9 knockdown significantly reduced mitochondrial Complex I activity. METTL9 can be a promising molecular target to inhibit peritoneal dissemination of scirrhous gastric cancers. This report is the first to describe the relationship between METTL9 and cancer metastasis.

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DNAJA3/Tid1 Is Required for Mitochondrial DNA Maintenance and Regulates Migration and Invasion of Human Gastric Cancer Cells

Cancers ◽

10.3390/cancers12113463 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3463

Author(s):

Sheng-Fan Wang ◽

Kuo-Hung Huang ◽

Wei-Chuan Tseng ◽

Jeng-Fan Lo ◽

Anna Fen-Yau Li ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Cancer Patients ◽

Migration And Invasion ◽

Gastric Cancer Cells ◽

Cell Migration And Invasion ◽

Gastric Cancers ◽

Gastric Cancer Patients

Background: Gastric cancer is a common health issue. Deregulated cellular energetics is regarded as a cancer hallmark and mitochondrial dysfunction might contribute to cancer progression. Tid1, a mitochondrial co-chaperone, may play a role as a tumor suppressor in various cancers, but the role of Tid1 in gastric cancers remains under investigated. Methods: The clinical TCGA online database and immunohistochemical staining for Tid1 expression in tumor samples of gastric cancer patients were analyzed. Tid1 knockdown by siRNA was applied to investigate the role of Tid1 in gastric cancer cells. Results: Low Tid1 protein-expressing gastric cancer patients had a poorer prognosis and higher lymph node invasion than high Tid1-expressing patients. Knockdown of Tid1 did not increase cell proliferation, colony/tumor sphere formation, or chemotherapy resistance in gastric cancer cells. However, Tid1 knockdown increased cell migration and invasion. Moreover, Tid1 knockdown reduced the mtDNA copy number of gastric cancer cells. In addition, the Tid1-galectin-7-MMP-9 axis might be associated with Tid1 knockdown–induced cell migration and invasion of gastric cancer cells. Conclusions: Tid1 is required for mtDNA maintenance and regulates migration and invasion of gastric cancer cells. Tid1 deletion may be a poor prognostic factor in gastric cancers and could be further investigated for development of gastric cancer treatments.

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Leptin Receptor (LEPR) promotes proliferation, migration, and invasion and inhibits apoptosis in hepatocellular carcinoma by regulating ANXA7

Cancer Cell International ◽

10.1186/s12935-020-01641-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

He Huang ◽

Jun Zhang ◽

Fei Ling ◽

Yuhong Huang ◽

Min Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Cancer Metastasis ◽

Leptin Receptor ◽

Migration And Invasion ◽

Metastatic Cells ◽

Promising Therapeutic Target ◽

F Cells ◽

Underlying Mechanisms

Abstract Background Leptin Receptor (LEPR) has been suggested to have several roles in cancer metastasis. However, the role of LEPR and its underlying mechanisms in lymphatic metastasis of hepatocarcinoma have not yet been studied. Methods We performed bioinformatics analysis, qRT-PCR, western blotting, immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent, coimmunoprecipitation assays and a series of functional assays to investigate the roles of LEPR in hepatocellular carcinoma. Results We discovered that LEPR was highly expressed in liver cancer tissues, and the expression of LEPR in Hca-F cells was higher than that in Hca-P cells. Furthermore, LEPR promotes the proliferation, migration and invasion and inhibits the apoptosis of hepatocarcinoma lymphatic metastatic cells. Further studies indicated that LEPR interacts with ANXA7. Mechanistically, LEPR regulated ERK1/2 and JAK2/STAT3 expression via ANXA7 regulation. Conclusions These findings unveiled a previously unappreciated role of LEPR in the regulation of lymphatic metastatic hepatocellular carcinoma, assigning ANXA7-LEPR as a promising therapeutic target for liver cancer treatments.

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DETERMINATION OF P53 GENE CODON 72 POLYMORPHISMS IN PATIENTS WITH GASTRIC CANCER

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2013.2.2 ◽

2013 ◽

pp. 11-17

Author(s):

Thi Tuy Ha Nguyen ◽

Thi Minh Thi Ha

Keyword(s):

Gastric Cancer ◽

Cancer Patients ◽

P53 Gene ◽

Diffuse Gastric Cancer ◽

Codon 72 ◽

Cancer Group ◽

Pcr Rflp ◽

Gastric Cancer Patients ◽

The Relationship

Background: The role of p53 gene in the gastric cancer is still controversial. This study is aimed at determining the rate of the p53 gene codon 72 polymorphisms in gastric cancer patients and evaluating the relationship between these polymorphisms and endoscopic and histopathological features of gastric cancer. Patients and methods: Sixty eight patients with gastric cancer (cases) and one hundred and thirty six patients without gastric cancer (controls) were enrolled. p53 gene codon 72 polymorphisms were determined by PCR-RFLP technique with DNA extracted from samples of gastric tissue. Results: In the group of gastric cancer, Arginine/Argnine, Arginine/Proline and Proline/Proline genotypes were found in 29.4%, 42.7% and 27.9%, respectively. The differences of rates were not statistically significant between cases and controls (p > 0,05). In males, the Proline/Proline genotype was found in 38.1% in patients with gastric cancer and more frequent in patients without gastric cancer (15.7%, p = 0,01). An analysis of ROC curve showed that the cut-off was the age of 52 in the Proline/Proline genotype, but it was 65 years old in the Arginine/Proline genotype. The Proline/Proline genotype was found in 41.9% in Borrmann III/IV gastric cancer, this rate was higher than Borrmann I/II gastric cancer (16.2%, p = 0.037) and also higher than controls (18.4%, p = 0,01). The rate of Proline/Proline genotype was 41.7% in the diffuse gastric cancer, it was higher than in controls (p = 0,023). Conclusion: No significative difference of rate was found in genotypes between gastric cancer group and controls. However, there was the relationship between Proline/Proline genotype and gastric cancer in males, Borrmann types of gastric cancer, the diffuse gastric cancer. Key words: polymorphism, codon 72, p53 gene, PCR - RFLP, gastric cancer.

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Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽

10.3390/cells10030558 ◽

2021 ◽

Vol 10 (3) ◽

pp. 558

Author(s):

Jin Kyung Seok ◽

Eun-Hee Hong ◽

Gabsik Yang ◽

Hye Eun Lee ◽

Sin-Eun Kim ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Autophagic Flux ◽

Oxidized Phospholipids ◽

Mcf7 Cells ◽

Mesenchymal Transition ◽

Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

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Erianthridin suppresses non-small-cell lung cancer cell metastasis through inhibition of Akt/mTOR/p70S6K signaling pathway

Scientific Reports ◽

10.1038/s41598-021-85675-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sutthaorn Pothongsrisit ◽

Kuntarat Arunrungvichian ◽

Yoshihiro Hayakawa ◽

Boonchoo Sritularak ◽

Supachoke Mangmool ◽

...

Keyword(s):

Lung Cancer ◽

Cell Migration ◽

Protein Kinase ◽

Small Cell Lung Cancer ◽

Cancer Metastasis ◽

Small Cell ◽

Migration And Invasion ◽

Lung Cancer Cell ◽

Small Cell Lung ◽

Cell Metastasis

AbstractCancer metastasis is a major cause of the high mortality rate in lung cancer patients. The cytoskeletal rearrangement and degradation of extracellular matrix are required to facilitate cell migration and invasion and the suppression of these behaviors is an intriguing approach to minimize cancer metastasis. Even though Erianthridin (ETD), a phenolic compound isolated from the Thai orchid Dendrobium formosum exhibits various biological activities, the molecular mechanism of ETD for anti-cancer activity is unclear. In this study, we found that noncytotoxic concentrations of ETD (≤ 50 μM) were able to significantly inhibit cell migration and invasion via disruption of actin stress fibers and lamellipodia formation. The expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 was markedly downregulated in a dose-dependent manner after ETD treatment. Mechanistic studies revealed that protein kinase B (Akt) and its downstream effectors mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K) were strongly attenuated. An in silico study further demonstrated that ETD binds to the protein kinase domain of Akt with both hydrogen bonding and van der Waals interactions. In addition, an in vivo tail vein injection metastasis study demonstrated a significant effect of ETD on the suppression of lung cancer cell metastasis. This study provides preclinical information regarding ETD, which exhibits promising antimetastatic activity against non-small-cell lung cancer through Akt/mTOR/p70S6K-induced actin reorganization and MMPs expression.

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Ovalitenone Inhibits the Migration of Lung Cancer Cells via the Suppression of AKT/mTOR and Epithelial-to-Mesenchymal Transition

Molecules ◽

10.3390/molecules26030638 ◽

2021 ◽

Vol 26 (3) ◽

pp. 638

Author(s):

Kittipong Sanookpan ◽

Nongyao Nonpanya ◽

Boonchoo Sritularak ◽

Pithi Chanvorachote

Keyword(s):

Lung Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Colony Formation ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

A549 Cells ◽

Lung Cancer Cells ◽

Migration And Invasion ◽

Mesenchymal Transition

Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.

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Long non-coding RNA AFAP1-AS1 accelerates lung cancer cells migration and invasion by interacting with SNIP1 to upregulate c-Myc

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00562-y ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Yu Zhong ◽

Liting Yang ◽

Fang Xiong ◽

Yi He ◽

Yanyan Tang ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Metastasis ◽

Lung Cancer Cells ◽

Migration And Invasion ◽

Lung Cancer Patients ◽

Lung Cancer Metastasis ◽

Non Coding Rna ◽

Long Non Coding Rna

AbstractActin filament associated protein 1 antisense RNA 1 (named AFAP1-AS1) is a long non-coding RNA and overexpressed in many cancers. This study aimed to identify the role and mechanism of AFAP1-AS1 in lung cancer. The AFAP1-AS1 expression was firstly assessed in 187 paraffin-embedded lung cancer and 36 normal lung epithelial tissues by in situ hybridization. The migration and invasion abilities of AFAP1-AS1 were investigated in lung cancer cells. To uncover the molecular mechanism about AFAP1-AS1 function in lung cancer, we screened proteins that interact with AFAP1-AS1 by RNA pull down and the mass spectrometry analyses. AFAP1-AS1 was highly expressed in lung cancer clinical tissues and its expression was positively correlated with lung cancer patients’ poor prognosis. In vivo experiments confirmed that AFAP1-AS1 could promote lung cancer metastasis. AFAP1-AS1 promoted lung cancer cells migration and invasion through interacting with Smad nuclear interacting protein 1 (named SNIP1), which inhibited ubiquitination and degradation of c-Myc protein. Upregulation of c-Myc molecule in turn promoted the expression of ZEB1, ZEB2, and SNAIL gene, which ultimately enhanced epithelial to mesenchymal transition (EMT) and lung cancer metastasis. Understanding the molecular mechanism by which AFAP1-AS1 promotes lung cancer’s migration and invasion may provide novel therapeutic targets for lung cancer patients’ early diagnosis and therapy.

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Targeting the Metabolic Adaptation of Metastatic Cancer

Cancers ◽

10.3390/cancers13071641 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1641

Author(s):

Josep Tarragó-Celada ◽

Marta Cascante

Keyword(s):

Colorectal Cancer ◽

Cancer Metastasis ◽

Metastatic Cancer ◽

Breast Cancer Metastasis ◽

Metabolic Inhibitors ◽

Current Status ◽

Metabolic Adaptation ◽

Metastatic Cells ◽

Colorectal Cancer Metastasis ◽

Metastatic Process

Metabolic adaptation is emerging as an important hallmark of cancer and metastasis. In the last decade, increasing evidence has shown the importance of metabolic alterations underlying the metastatic process, especially in breast cancer metastasis but also in colorectal cancer metastasis. Being the main cause of cancer-related deaths, it is of great importance to developing new therapeutic strategies that specifically target metastatic cells. In this regard, targeting metabolic pathways of metastatic cells is one of the more promising windows for new therapies of metastatic colorectal cancer, where still there are no approved inhibitors against metabolic targets. In this study, we review the recent advances in the field of metabolic adaptation of cancer metastasis, focusing our attention on colorectal cancer. In addition, we also review the current status of metabolic inhibitors for cancer treatment.

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Long Noncoding RNA Lnc-TLN2-4:1 Suppresses Gastric Cancer Metastasis and Is Associated with Patient Survival

Journal of Oncology ◽

10.1155/2020/8681361 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yuyun Wu ◽

Ningbo Hao ◽

Suming Wang ◽

Xin Yang ◽

Yufeng Xiao ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Noncoding Rna ◽

Tumor Metastasis ◽

Cancer Metastasis ◽

Survival Rates ◽

Migration And Invasion ◽

Poor Overall Survival ◽

Low Expression ◽

Overall Survival Rates

Gastric cancer (GC) is one of the most common malignancies worldwide, and the tumor metastasis leads to poor outcomes of GC patients. Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules that play a crucial role in tumor metastasis. However, the biological function and underlying mechanism of numerous lncRNAs in GC metastasis remain largely unclear. Here, we report a novel lncRNA, lnc-TLN2-4:1, whose expression is decreased in GC tissue versus matched normal tissue, and its low expression is involved in the lymph node and distant metastases of GC, as well as poor overall survival rates of GC patients. We further found that lnc-TLN2-4:1 inhibits the ability of GC cells to migrate and invade but does not influence GC cell proliferation and confirmed that lnc-TLN2-4:1 is mainly located in the cytoplasm of GC cells. We then found that lnc-TLN2-4:1 increases the mRNA and protein expression of TLN2 in GC cells and there is a positive correlation between the expression of lnc-TLN2-4:1 and TLN2 mRNA in GC tissue. Collectively, we identified a novel lncRNA, lnc-TLN2-4:1, in GC, where lnc-TLN2-4:1 represses cell migration and invasion. The low expression of lnc-TLN2-4:1 is associated with poor overall survival rates of GC patients. These suggest that lnc-TLN2-4:1 may be a tumor suppressor during GC metastasis.

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