C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin αv

AbstractPancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related death. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Here we showed that C1GALT1 was overexpressed in 85% (107/126) of PDAC tumors compared with adjacent non-tumor tissues. High expression of C1GALT1 was associated with poor disease-free and overall survival (n = 99). C1GALT1 knockdown using siRNA suppressed cell viability, migration, and invasion as well as increased gemcitabine sensitivity in PDAC cells. In contrast, C1GALT1 overexpression enhanced cell migration and invasion. In subcutaneous and pancreatic orthotopic injection models, C1GALT1 knockdown decreased tumor growth and metastasis of PDAC cells in NOD/SCID mice. Mechanistically, C1GALT1 knockdown dramatically suppressed cell-extracellular matrix (ECM) adhesion, which was associated with decreased phosphorylation of FAK at Y397/Y925 and changes in O-glycans on integrins including the β1, αv, and α5 subunits. Using functional blocking antibodies, we identified integrin αv as a critical factor in C1GALT1-mediated invasiveness of PDAC cells. In conclusion, this study not only reveals that C1GALT1 could be a potential therapeutic target for PDAC but also provides novel insights into the role of O-glycosylation in the α subunits of integrins.

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KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

BioMed Research International ◽

10.1155/2021/8249293 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Jing Chen ◽

Cui-Cui Zhao ◽

Fei-Ran Chen ◽

Guo-Wei Feng ◽

Fei Luo ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Pancreatic Ductal Adenocarcinoma ◽

Disease Free Survival ◽

High Expression ◽

Ductal Adenocarcinoma ◽

Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

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High expression of diffuse panbronchiolitis critical region 1 gene promotes cell proliferation, migration and invasion in pancreatic ductal adenocarcinoma

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2017.12.031 ◽

2018 ◽

Vol 495 (2) ◽

pp. 1908-1914 ◽

Cited By ~ 2

Author(s):

Jiayi Yan ◽

Guanghui Chen ◽

Xuesong Zhao ◽

Fangying Chen ◽

Ting Wang ◽

...

Keyword(s):

Cell Proliferation ◽

Pancreatic Ductal Adenocarcinoma ◽

Critical Region ◽

High Expression ◽

Ductal Adenocarcinoma ◽

Migration And Invasion ◽

Diffuse Panbronchiolitis

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Nesfatin-1/Nucleobindin-2 Is a Potent Prognostic Marker and Enhances Cell Proliferation, Migration, and Invasion in Bladder Cancer

Disease Markers ◽

10.1155/2018/4272064 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Guang-Ming Liu ◽

Zi-Qiang Xu ◽

Hong-Shun Ma

Keyword(s):

Bladder Cancer ◽

Poor Prognosis ◽

High Expression ◽

Migration And Invasion ◽

Wound Healing Assay ◽

Transwell Assay ◽

T24 Cells ◽

Tumor Growth And Metastasis

In recent researches, high expression of nesfatin-1/nucleobindin-2 (NUCB2) is linked to poor prognosis in prostate and colon cancer due to the enhancement in proliferation, migration, and invasion. However, the role of nesfatin-1 in bladder cancer is not clear. In this study, we examined the expression of NUCB2 in bladder cancer using immunohistochemistry and observed that its high expression was associated with recurrence and metastasis. In addition, the transwell assay and wound healing assay showed that cell migration and invasion were decreased with NUCB2 knockdown in T24 and 5637 cells. In vivo, tumor growth and metastasis were inhibited with shRNA treatment in T24 cells. Those results showed that NUCB2 played an important role in bladder cancer and could be considered a potent prognostic factor in bladder cancer.

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CIRBP Knockdown Attenuates Tumourigenesis and Improves the Chemosensitivity of Pancreatic Cancer via the Downregulation of DYRK1B

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.667551 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xiang Chen ◽

Hongyu Xie ◽

Xin Wang ◽

Zhinan Zheng ◽

Sanqing Jin

Keyword(s):

Rna Binding ◽

Treatment Options ◽

Ductal Adenocarcinoma ◽

Pancreatic Tumors ◽

Migration And Invasion ◽

Dual Specificity ◽

Tumor Tissues ◽

Gemcitabine Treatment

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide with very limited treatment options. Cold-inducible RNA binding protein (CIRBP) plays promoting roles in several types of cancers, but its function remains unclear in PDAC. Here, we found that the expression of CIRBP was upregulated in PDAC tumor tissues and was significantly associated with poor prognosis. Knockdown of CIRBP in PANC-1 and SW1990 cells inhibited proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Moreover, CIRBP knockdown enhanced the antitumour effects of gemcitabine treatment in PANC-1 and SW1990 cells, whereas CIRBP overexpression exerted the opposite effects. Mechanistically, CIRBP promoted PDAC malignancy and chemoresistance via upregulation of dual-specificity tyrosine-Y-phosphorylation regulated kinase 1B (DYRK1B). Indeed, knockdown of CIRBP sensitized pancreatic tumors to gemcitabine treatment by diminishing DYRK1B expression and increasing the ratio of ERK/p38 activity. Our findings suggest that CIRBP overexpression facilitates PDAC progression and gemcitabine resistance by upregulating DYRK1B expression and inhibiting the ERK/p38 signaling pathway, highlighting CIRBP as a potential new therapeutic target for PDAC.

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A positive feedback between HIF1α and lysyl oxidase-like 2 dictates the Warburg Effect in Pancreatic Cancer

10.21203/rs.3.rs-360740/v1 ◽

2021 ◽

Author(s):

Rongkun Li ◽

Yahui Wang ◽

Lili Zhu ◽

Xiaoxin Zhang ◽

Dejun Liu ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Positive Feedback ◽

Warburg Effect ◽

Lysyl Oxidase ◽

Ductal Adenocarcinoma ◽

Migration And Invasion ◽

Cancer Aggressiveness ◽

Tumor Growth And Metastasis ◽

The Warburg Effect

Abstract Background Hypoxic microenvironment is common in solid tumors, particularly in pancreatic ductal adenocarcinoma (PDAC). The Warburg effect is known to facilitate cancer aggressiveness and has long been linked to hypoxia, yet the underlying mechanism remains largely unknown. Methods The expression pattern and prognostic value of LOXL2 was analyzed by immunohistochemistry. The effects of LOXL2 on cancer cell proliferation, migration, and invasion in vitro, tumor growth and metastasis in vivo were investigated by genetic manipulation of LOXL2 expression in human PDAC cell lines. The effects of LOXL2 on aerobic glycolysis were examined by glucose uptake, lactate production, and Seahorse Flux Analyzer. Quantitative real-time PCR, western blotting, immunofluorescence and other techniques were conducted to identify molecular mechanism. Results Lysyl oxidase-like 2 (LOXL2) is a hypoxia-responsive gene and is essential for the Warburg effect in pancreatic ductal adenocarcinoma (PDAC). LOXL2 stabilizes hypoxia-inducible factor 1α (HIF1α) from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, thereby facilitating the transcription of multiple glycolytic genes. Therefore, a positive feedback loop is existed between LOXL2 and HIF1α that facilitates glycolytic metabolism under hypoxia. LOXL2 couples the Warburg effect to tumor growth and metastasis in PDAC. Hijacking glycolysis largely compromises LOXL2-induced oncogenic activities. Conclusion Our results identify a hitherto unknown hypoxia-LOXL2-HIF1α axis in regulating the Warburg effect and provide an intriguing drug target for PDAC therapy.

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The role of Notch ligand Jagged1 in osteosarcoma proliferation, metastasis, and recurrence

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02372-y ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Jianping Zhang ◽

Na Li ◽

Siyu Lu ◽

Yanling Chen ◽

Lequn Shan ◽

...

Keyword(s):

Bone Cancer ◽

High Expression ◽

Migration And Invasion ◽

Osteosarcoma Cells ◽

Metastatic Recurrence ◽

Real Time Quantitative Pcr ◽

Metastatic Osteosarcoma ◽

Tumor Tissues ◽

Lower Ability

Abstract Background Osteosarcoma is the most common primary bone cancer occurring in young adults and the 5-year survival rate of patients with metastatic osteosarcoma is less than 30% due to high metastatic recurrence and drug resistance. Notch is a highly conserved cell to cell signaling pathway in evolution, and Jagged1 is an important ligand of Notch. Although some studies have found that Notch receptors and ligands including Jagged1 were highly expressed in osteosarcoma tissues and osteosarcoma cells, the role of Jagged1 in osteosarcoma progression and metastasis are still not clear. Methods Tumor tissues were collected from 68 patients and immunohistochemical staining was employed to group these patients by expression of Jagged1. Real-time quantitative PCR and Western blotting were used to detect the expression of Jagged1. We used siRNA to knockdown the expression of Jagged1 in F5M2 cells. Colony formation assay and MTT were employed to detect and analyze the proliferation of F5M2 cells with or without knockdown of Jagged1. Transwell assay were used to detect the migration and invasion of F5M2 cells. Results In this study, we found that the high expression of Jagged1 is closely related to the metastasis and recurrence of osteosarcoma in 68 clinical specimens. The expression of Jagged1 in F5M2 cells with high metastasis was significantly higher than that in F4 cells with low metastasis. Knockdown of Jagged1 led to lower ability of proliferation, migration, and invasion in F5M2 cells. Conclusion The high expression of Jagged1 is closely related to the metastasis and recurrence of osteosarcoma. Knockdown of Jagged1 significantly reduced the proliferation, migration, and invasion of osteosarcoma cells. Our results suggested that knockdown of Jagged1 may be a potentially effective treatment for metastatic osteosarcoma.

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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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LncRNA MAFG-AS1 regulates miR-125b-5p/SphK1 axis to promote the proliferation, migration, and invasion of bladder cancer cells

Human Cell ◽

10.1007/s13577-020-00470-3 ◽

2021 ◽

Author(s):

Chenye Tang ◽

Yuntao Wu ◽

Xiao Wang ◽

Kean Chen ◽

Zhiling Tang ◽

...

Keyword(s):

Cell Proliferation ◽

Bladder Cancer ◽

Migration And Invasion ◽

Inhibitory Effects ◽

Potential Therapeutic Target ◽

Downstream Target ◽

Transwell Invasion Assay ◽

Tumor Tissues ◽

Bladder Cancer Cells ◽

Luciferase Activity Assay

AbstractMAFG-AS1 is an oncogenic lncRNA in multiple types of cancer. However, its role in bladder cancer (BC) remains unclear. The present study aimed to investigate the function of MAFG-AS1 in BC. BC and paired non-tumor tissues were collected. Two BC cell lines HT01197 and HT-1376 were used. Dual luciferase activity assay, RT-qPCR, western blot, CCK-8, transwell invasion assay, and wound healing assay were performed. We found that MAFG-AS1 was significantly up-regulated in BC tissues and predicted a poor survival rate. MAFG-AS1 interacted with miR-125b-5p. However, the expression levels of MAFG‑AS1 and miR-125b-5p were not obviously correlated in BC tissues, and MAFG‑AS1 and miR-125b-5p did not regulate the expression of each other. Interestingly, we found that SphK1, a downstream target of miR-125b-5p, was negatively correlated with miR-125b-5p, while it was positively correlated with MAFG-AS1 across BC tissues. In addition, overexpression of MAFG‑AS1 upregulated the expression of SphK1 in BC cells, and attenuated the inhibitory effects of miR-125b-5p on the expression of SphK1. Functional assays showed that overexpression of MAFG‑AS1 promoted BC cell proliferation, migration, and invasion, while its effects were attenuated by overexpression of miR-125b-5p. Moreover, overexpression of miR-125b-5p inhibited BC cell proliferation, migration, and invasion, while its effects were alleviated by overexpression of SphK1. Taken together, our findings demonstrated that MAFG-AS1 has an oncogenic role in BC by regulating the miR-125b-5p/SphK1 axis. MAFG-AS1 might serve as a good diagnostic marker and a potential therapeutic target of BC.

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Expression and clinical significance of CMTM1 in hepatocellular carcinoma

Open Medicine ◽

10.1515/med-2021-0221 ◽

2021 ◽

Vol 16 (1) ◽

pp. 217-223

Author(s):

Xin Song ◽

Shidong Zhang ◽

Run Tian ◽

Chuanjun Zheng ◽

Yuge Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Transmembrane Domain ◽

Disease Free Survival ◽

Clinicopathological Characteristics ◽

The Cancer Genome Atlas ◽

High Expression ◽

Chi Square ◽

Tumor Tissues ◽

The Relationship ◽

Low Expression

Abstract Background CKLF Like Marvel Transmembrane Domain Containing 1 (CMTM1) plays a role in breast cancer and lung cancer, but studies on the occurrence and development of CMTM1 in hepatocellular carcinoma (HCC) have not been reported. Methods The Cancer Genome Atlas (TCGA) database and immunohistochemistry (IHC) were used to detect CMTM1 expression in HCC tissues. The relationship between CMTM1 expression and the clinicopathological characteristics of HCC patients was analyzed by chi-square test, and the relationship between CMTM1 expression and the prognosis of HCC patients was tested by the Kaplan–Meier model. Results Bioinformatics analysis showed that the mRNA expression of CMTM1 was upregulated in HCC tissues, and low expression of CMTM1 is associated with longer disease-free survival in patients with HCC. Similarly, the survival time of HCC patients in CMTM1 high expression group was significantly shorter than that in CMTM1 low expression group. IHC detection indicated that CMTM1 protein was highly expressed in both HCC and adjacent non-tumor tissues, with a positive expression in 84% (63/75) of HCC tissues and 89.3% (67/75) of adjacent non-tumor tissues. Moreover, CMTM1 expression was related to family history and TNM stage of HCC patients (P < 0.05), but had no relationship with other clinicopathological characteristics. The survival analysis based on IHC results showed that the prognosis of HCC patients in CMTM1 negative group was significantly poorer than that in CMTM1 positive group (P < 0.05). Conclusion CMTM1 has a high expression in HCC tissues and is related to the prognosis of HCC patients.

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