scholarly journals Annexin A1 Expression Is Associated with Epithelial–Mesenchymal Transition (EMT), Cell Proliferation, Prognosis, and Drug Response in Pancreatic Cancer

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 653
Author(s):  
Masanori Oshi ◽  
Yoshihisa Tokumaru ◽  
Swagoto Mukhopadhyay ◽  
Li Yan ◽  
Ryusei Matsuyama ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Biology ◽  
Drug Response ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Annexin A1 ◽  
Mesenchymal Transition ◽  
Gene Sets ◽  
Apoptosis Protein

Annexin A1 (ANXA1) is a calcium-dependent phospholipid-binding protein overexpressed in pancreatic cancer (PC). ANXA1 expression has been shown to take part in a wide variety of cancer biology, including carcinogenesis, cell proliferation, invasion, apoptosis, and metastasis, in addition to the initially identified anti-inflammatory effect in experimental settings. We hypothesized that ANXA1 expression is associated with cell proliferation and survival in PC patients. To test this hypothesis, we analyzed 239 PC patients in The Cancer Genome Atlas (TCGA) and GSE57495 cohorts. ANXA1 expression correlated with epithelial–mesenchymal transition (EMT) but weakly with angiogenesis in PC patients. ANXA1-high PC was significantly associated with a high fraction of fibroblasts and keratinocytes in the tumor microenvironment. ANXA1 high PC enriched multiple malignant gene sets, including hypoxia, tumor necrosis factor (TNF)-α signaling via nuclear factor-kappa B (NF-kB), and MTORC1, as well as apoptosis, protein secretion, glycolysis, and the androgen response gene sets consistently in both cohorts. ANXA1 expression was associated with TP53 mutation alone but associated with all KRAS, p53, E2F, and transforming growth factor (TGF)-β signaling pathways and also associated with homologous recombination deficiency in the TCGA cohort. ANXA1 high PC was associated with a high infiltration of T-helper type 2 cells in the TME, with advanced histological grade and MKI67 expression, as well as with a worse prognosis regardless of the grade. ANXA1 expression correlated with a sensitivity to gemcitabine, doxorubicin, and 5-fluorouracil in PC cell lines. In conclusion, ANXA1 expression is associated with EMT, cell proliferation, survival, and the drug response in PC.

scholarly journals High Expression of miR-34a Associated with Less Aggressive Cancer Biology but Not with Survival in Breast Cancer

2020 ◽  
Vol 21 (9) ◽  
pp. 3045 ◽  
Author(s):  
Yoshihisa Tokumaru ◽  
Eriko Katsuta ◽  
Masanori Oshi ◽  
Judith C. Sporn ◽  
Li Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Biology ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Taxonomy ◽  
The Cancer Genome Atlas ◽  
P53 Pathway ◽  
Mesenchymal Transition ◽  
Gene Sets ◽  
Aggressive Cancer

Most breast cancer (BC) patients succumb to metastatic disease. MiR-34a is a well-known tumor suppressive microRNA which exerts its anti-cancer functions by playing a role in p53, apoptosis induction, and epithelial-mesenchymal transition (EMT) suppression. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) cohorts were used to test our hypothesis that miR-34a high BCs translate to less aggressive cancer biology and better survival in large cohorts. There was no association between miR-34a expression levels and clinicopathological features of BC patients except for HER2 positivity. MiR-34a high expressing tumors were associated with lower Nottingham pathological grades and lower MKI67 expression. In agreement, high miR-34a tumors demonstrated lower GSVA scores of cell cycle and cell proliferation-related gene sets. High miR-34a tumors enriched the p53 pathway and apoptosis gene sets. Unexpectedly, high miR-34a tumors also associated with elevated EMT pathway score and ZEB1 and two expressions. MiR-34a expression did not associate with any distant metastasis. Further, high miR-34a tumors did not associate with better survival compared with miR-34a low tumors. In conclusion, the clinical relevance of miR-34a high expressing tumors was associated with suppressed cell proliferation, enhanced p53 pathway and apoptosis, but enhanced EMT and these findings did not reflect better survival outcomes in large BC patient cohorts.

scholarly journals Keratin 17 Suppresses Cell Proliferation and Epithelial-Mesenchymal Transition in Pancreatic Cancer

2020 ◽  
Vol 7 ◽  
Author(s):  
Yong Zeng ◽  
Min Zou ◽  
Yan Liu ◽  
Keting Que ◽  
Yunbing Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Pancreatic Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Cancer Cell Proliferation ◽  
Cycle Progression ◽  
Mesenchymal Transition

Keratin 17 (K17), a member of type I acidic epithelial keratin family, has been reported to be upregulated in many malignant tumors and to be involved in promoting the development of tumors. However, the precise role of K17 in progression of pancreatic cancer is still unknown. In this study, we found that K17 expression was highly expressed in pancreatic cancer tissues and cell lines and that upregulated expression was associated with the pathological grade and poor prognosis. K17 expression served as an independent predictor of pancreatic cancer survival. Meanwhile, we showed that knocking down K17 induced pancreatic cancer cell proliferation, colony formation and tumor growth in xenografts in mice. However, K17 upregulation inhibited pancreatic cancer cell proliferation and colony formation. Further mechanistic study revealed that K17 knockdown promoted cell cycle progression by upregulating CyclinD1 expression and repressed cell apoptosis. However, K17 upregulation suppressed cell cycle progression by decreasing CyclinD1 expression, and induced apoptosis by increasing the levels of cleaved Caspase3. In addition, K17 knockdown promoted pancreatic cancer cell migration and invasion, but K17 upregulation suppressed cell migration and invasion. Moreover, knocking down K17 promoted epithelial-mesenchymal transition (EMT) in pancreatic cancer cell by inhibiting E-cadherin expression and inducing Vimentin expression, and the effects of K17 upregulation were opposite to that of K17downregulation. Taken together, our findings suggest that K17 functions as a potential tumor suppressor, even though it is upregulated in pancreatic cancer.

scholarly journals Hyperglycemia promotes Snail-induced epithelial–mesenchymal transition of gastric cancer via activating ENO1 expression

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xin Xu ◽  
Bang Chen ◽  
Shaopu Zhu ◽  
Jiawei Zhang ◽  
Xiaobo He ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Gastrointestinal Malignancies ◽  
Mesenchymal Transition

Abstract Background Gastric cancer (GC) is one of the most common gastrointestinal malignancies worldwide. Emerging evidence indicates that hyperglycemia promotes tumor progression, especially the processes of migration, invasion and epithelial–mesenchymal transition (EMT). However, the underlying mechanisms of GC remain unclear. Method Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to detect the expression of glycolysis-related enzymes and EMT-related transcription factors. Small interfering RNA (siRNA) transfection was performed to decrease ENO1 expression. Immunohistochemistry (IHC), Western blot and qRT-PCR analyses were used to measure gene expression at the protein or mRNA level. CCK-8, wound-healing and Transwell assays were used to assess cell proliferation, migration and invasion. Results Among the glycolysis-related genes, ENO1 was the most significantly upregulated in GC, and its overexpression was correlated with poor prognosis. Hyperglycemia enhanced GC cell proliferation, migration and invasion. ENO1 expression was also upregulated with increasing glucose concentrations. Moreover, decreased ENO1 expression partially reversed the effect of high glucose on the GC malignant phenotype. Snail-induced EMT was promoted by hyperglycemia, and suppressed by ENO1 silencing. Moreover, ENO1 knockdown inhibited the activation of transforming growth factor β (TGF-β) signaling pathway in GC. Conclusions Our results indicated that hyperglycemia induced ENO1 expression to trigger Snail-induced EMT via the TGF-β/Smad signaling pathway in GC.

Long noncoding RNA XIST regulates the EGF receptor to promote TGF-β1-induced epithelial–mesenchymal transition in pancreatic cancer

2020 ◽  
Vol 98 (2) ◽  
pp. 267-276 ◽  
Author(s):  
Lei Zou ◽  
Feng-Rong Chen ◽  
Ren-Pin Xia ◽  
Hua-Wei Wang ◽  
Zhen-Rong Xie ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Clinical Specimens ◽  
Qrt Pcr ◽  
Reporter Assays ◽  
Tgf Β1

Background: This study focuses on the lncRNA XIST (X inactive-specific transcript), an lncRNA involved in multiple human cancers, and investigates the functional significance of XIST and the molecular mechanisms underlying the epithelial–mesenchymal transition (EMT) in pancreatic cancer (PC). Methods: Clinical specimens from 25 patients as well as 5 human PC cell lines were analyzed for XIST, YAP, and microRNA(miR)-34a by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. To investigate how XIST influences cell proliferation, invasiveness, and apoptosis in PC, we performed the CCK-8 assays, Transwell assays, and flow cytometry. Luciferase reporter assays, qRT-PCR, and Western blot were applied to prove that miR-34a directly binds to XIST. Results: Up-regulation of XIST and Yes associated protein (YAP) and down-regulation of miR-34a were consistently observed in the clinical specimens and PC cell lines. Silencing XIST reduced the expression of YAP and suppressed transforming growth factor (TGF)-β1-induced EMT, while over-expression of XIST increased the expression of YAP and promoted EMT. In addition, inhibition of epidermal growth factor receptor (EGFR) hampered the XIST-promoted EMT. The results from the luciferase reporter assays confirmed that miR-34a directly targets XIST and suggested that XIST regulates cell proliferation, invasiveness, and apoptosis in PC by sponging miR-34a. Conclusions: XIST promotes TGF-β1-induced EMT by regulating the miR-34a–YAP–EGFR axis in PC.

scholarly journals Transcriptomic Profile of Lymphovascular Invasion, a Known Risk Factor of Pancreatic Ductal Adenocarcinoma Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2033 ◽  
Author(s):  
Hideo Takahashi ◽  
Eriko Katsuta ◽  
Li Yan ◽  
Yoshihisa Tokumaru ◽  
Matthew H.G. Katz ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Risk Factor ◽  
Cancer Biology ◽  
Independent Risk Factor ◽  
Lymphovascular Invasion ◽  
Transforming Growth Factor ◽  
Gene Set Enrichment Analysis ◽  
Enrichment Score ◽  
Tgf Beta ◽  
Mesenchymal Transition

Lymphovascular invasion (LVI) is an aggressive pathologic feature and considered a risk factor for distant metastasis. We hypothesized that pancreatic ductal adenocarcinomas (PDACs) with LVI are associated with shorter survival, as well as aggressive cancer biology and lymphangiogenesis in transcriptomic analysis. Utilizing the cancer genome atlas (TCGA)-PDAC cohort, we found that positive LVI was significantly associated with positive perineural invasion (PNI) (p = 0.023), and higher American Joint Committee on Cancer (AJCC) T (p = 0.017) and N (p < 0.001) categories. Furthermore, positive LVI was associated with shorter overall survival (OS) (p = 0.014) and was an independent risk factor of poor OS. Although there was no association between LVI status and lymphangiogenesis, epithelial-mesenchymal transition (EMT), or metastasis-related genes, Gene Set Enrichment Analysis revealed a strong association with cell-proliferation-related gene sets such as mitotic spindles (Normalized enrichment score (NES) = 1.76, p = 0.016) and G2/M checkpoints (NES = 1.75, p = 0.036), as well as with transforming growth factor beta (TGF-beta) signaling (NES = 1.61, p = 0.043), which is a known mechanism of metastasis in PDACs. In conclusion, positive LVI was an independent risk factor of poor OS in PDACs. We found that PDACs with LVI were possibly associated with accelerated cell proliferation and enhanced TGF-beta signaling independent of lymphangiogenesis. Transcriptomic profiling elucidates more precise tumor biology of LVI-positive PDACs.

scholarly journals Anticancer Effects of Midazolam on Lung and Breast Cancers by Inhibiting Cell Proliferation and Epithelial-Mesenchymal Transition

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1396
Author(s):  
Hsin-Ling Lu ◽  
King-Chuen Wu ◽  
Char-Wen Chen ◽  
Hong-Kai Weng ◽  
Bu-Miin Huang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
New Drugs ◽  
Cancer Cell Proliferation ◽  
Breast Cancers ◽  
Sedative Drug ◽  
Peripheral Tissues ◽  
Mesenchymal Transition

Despite improvements in cancer treatments resulting in higher survival rates, the proliferation and metastasis of tumors still raise new questions in cancer therapy. Therefore, new drugs and strategies are still needed. Midazolam (MDZ) is a common sedative drug acting through the γ-aminobutyric acid receptor in the central nervous system and also binds to the peripheral benzodiazepine receptor (PBR) in peripheral tissues. Previous studies have shown that MDZ inhibits cancer cell proliferation but increases cancer cell apoptosis through different mechanisms. In this study, we investigated the possible anticancer mechanisms of MDZ on different cancer cell types. MDZ inhibited transforming growth factor β (TGF-β)-induced cancer cell proliferation of both A549 and MCF-7 cells. MDZ also inhibited TGF-β-induced cell migration, invasion, epithelial-mesenchymal-transition, and Smad phosphorylation in both cancer cell lines. Inhibition of PBR by PK11195 rescued the MDZ-inhibited cell proliferation, suggesting that MDZ worked through PBR to inhibit TGF-β pathway. Furthermore, MDZ inhibited proliferation, migration, invasion and levels of mesenchymal proteins in MDA-MD-231 triple-negative breast cancer cells. Together, MDZ inhibits cancer cell proliferation both in epithelial and mesenchymal types and EMT, indicating an important role for MDZ as a candidate to treat lung and breast cancers.

scholarly journals TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6204
Author(s):  
Meena U. Rajagopal ◽  
Shivani Bansal ◽  
Prabhjit Kaur ◽  
Shreyans K. Jain ◽  
Tatiana Altadil ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
High Resolution Mass Spectrometry ◽  
Ductal Adenocarcinoma ◽  
Resectable Pancreatic Cancer ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

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