TM4SF1 Regulates Pancreatic Cancer Migration and Invasion In Vitro and In Vivo

Background/Aims: The cell surface protein transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors and plays a major role in the development of cancer. We aimed to investigate the effects of TM4SF1 on the migration and invasion of pancreatic cancer in vitro and in vivo and explore its related molecular mechanisms. Methods: qRT-PCR and immunohistochemical analyses were used to measure the expression of TM4SF1 in pancreatic cancer tissues and adjacent tissues. TM4SF1 was silenced using siRNA and shRNA to investigate the role of this protein in the proliferation and metastasis of pancreatic cancer cells. MTS and Transwell assays were used to examine the effect of TM4SF1 on pancreatic cancer cell lines. The expression and activity of MMP-2 and MMP-9 were determined by qRT-PCR, western blots and gelatin zymography. In vivo, orthotopic pancreatic tumor models were used to examine the formation of metastasis. Results: qRT-PCR and immunohistochemical analyses showed that TM4SF1 was highly expressed in pancreatic cancer tissues compared with the adjacent tissues. In in vitro experiments the silencing of TM4SF1 reduced cell migration and invasion and down-regulated the expression and activity of MMP-2 and MMP-9. However, no significant difference in cell proliferation was detected after silencing TM4SF1. Additionally, knocking down TM4SF1 decreased the formation of lung and liver metastases in orthotopic pancreatic tumor models. Conclusion: Our results demonstrate that the expression of TM4SF1 is higher in pancreatic cancer tissues and pancreatic cancer cell lines than controls. Knockdown of TM4SF1 inhibited the migration and invasion of pancreatic cancer cells by regulating the expression and activity of MMP-2 and MMP-9, which suggests that TM4SF1 may play a significant role in metastasis in pancreatic cancer.

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PIK3R3 Promotes Metastasis of Pancreatic Cancer via ZEB1 Induced Epithelial-Mesenchymal Transition

Cellular Physiology and Biochemistry ◽

10.1159/000489382 ◽

2018 ◽

Vol 46 (5) ◽

pp. 1930-1938 ◽

Cited By ~ 8

Author(s):

Yun-Peng Peng ◽

Yi Zhu ◽

Ling-Di Yin ◽

Ji-Shu Wei ◽

Xin-Chun Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Epithelial Mesenchymal Transition ◽

Metastatic Cancer ◽

Regulatory Subunit ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

Cancer Tissues

Background/Aims: PIK3R3 is a regulatory subunit of phosphatidylinositol 3-kinase (PI3K) which plays an essential role in the metastasis of several types of cancer. However, whether PIK3R3 can promote the metastasis of pancreatic cancer (PC) is still unclear. In this study, we characterized the role of PIK3R3 in metastasis of PC and underlying potential mechanisms. Methods: RT-PCR, western blot, immunofluorescence (IF) and immunohistochemistry (IHC) were applied to investigate the expression of genes and proteins in different cell lines and tissues. To assess the function of PIK3R3 and related mechanisms, the cells with RNAi-mediated knockdown or overexpression were used to perform a series of in vitro and in vivo assays. Results: PIK3R3 was significantly overexpressed in pancreatic cancer tissues, especially in metastatic cancer tissues, as well as in pancreatic cancer cells. Functional assays suggested that overexpression or knockdown of PIK3R3 could respectively promote or suppress the migration and invasion of PC cells in vitro and in vivo. Further mechanism related studies demonstrated that ERK1/2-ZEB1 pathway-triggered epithelial-mesenchymal transition (EMT) might be responsible for the PIK3R3-induced PC cell migration and invasion. Conclusion: PIK3R3 could promote the metastasis of PC by facilitating ZEB1 induced EMT, and could act as a potential therapeutic target to limit PC metastasis.

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Long Non-coding RNA DLEU2L Targets miR-210-3p to Suppress Gemcitabine Resistance in Pancreatic Cancer Cells via BRCA2 Regulation

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.645365 ◽

2021 ◽

Vol 8 ◽

Author(s):

Fei Xu ◽

Heshui Wu ◽

Jiongxin Xiong ◽

Tao Peng

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Aerobic Glycolysis ◽

Critical Role ◽

Migration And Invasion ◽

Pancreatic Cell ◽

Clinical Issue ◽

Pancreatic Cancer Cells

Gemcitabine (GEM) resistance remains a challenging clinical issue to overcome in chemotherapy against pancreatic cancer. We previously demonstrated that miR-210 derived from pancreatic cancer stem cells enhanced the GEM-resistant properties of pancreatic cancer cells, thus identifying miR-210 as an oncogenic miRNA. Herein, we report the existence of an upstream effector that acts as a competing endogenous RNA (ceRNA) to miR-210. Bioinformatic screening was performed to identify lncRNAs with a binding relationship to miR-210. Overexpression and interference vectors were constructed to demonstrate the effect of ceRNA activity in pancreatic cell behavior, both in vitro and in vivo. DLEU2L (deleted in lymphocytic leukemia 2-like), which is expressed at low levels in pancreatic cancer tissues, was shown to exhibit a binding relationship with miR-210-3p. Overexpression of DLEU2L and silencing of miR-210-3p suppressed the proliferation, migration, and invasion of pancreatic cancer cells while promoting apoptosis. These effects occurred via the inhibition of the Warburg effect (aerobic glycolysis) and AKT/mTOR signaling. In addition, we showed that BRCA2 is a target gene of miR-210-3p, and the downregulation of miR-210-3p by DLEU2L effectively induced an upregulation of BRCA2 via the ceRNA mechanism. In vivo, DLEU2L overexpression and miR-210-3p interference suppressed pancreatic tumor progression, consistent with the results of in vitro studies. The findings of our study establish DLEU2L as a ceRNA to miR-210-3p and reveal the critical role of the DLEU2L/miR-210-3p crosstalk in targeting GEM resistance.

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METTL3 Promotes Pancreatic Tumor Progression Through Regulating the miR-196a/CPEB3 Axis

10.21203/rs.3.rs-101231/v1 ◽

2020 ◽

Author(s):

Pingping Ge ◽

Dong Fan ◽

Lei He ◽

Qiong Wu ◽

Jin Sun ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Progression ◽

Cancer Cells ◽

Pancreatic Tumor ◽

Luciferase Reporter ◽

Pancreatic Cancer Cells ◽

And Migration ◽

Proliferation And Migration

Abstract Background: Methyltransferase-like 3(METTL3)-mediated N6-methyladenosine (m6A) modification has been reported to regulate microRNAs maturation. Here, the study was designed to investigate the regulatory effect of m6A-dependent miRNA maturation on pancreatic cancer progression which is still limited before.Results: We found that METTL3 significantly upregulated in the pancreatic tumor tissues. Overexpression of METTL3 promoted cancer cell proliferation and migration in vitro and tumor progression in vivo. METTL3-mediated m6A modification facilitated miR-196a maturation in pancreatic cancer cells, and miR-196a increased the proliferation and migration of cancer cells in vitro. Luciferase reporter assay verified that cytoplasmic polyadenylation element binding protein 3 (CPEB3) was a direct target gene of miR-196a. In vivo studies proved that overexpression of miR-196a inhibited the anti-tumor effect of knockdown of METTL3, and overexpression of CPEB3 inhibited the miR-196a-enhanced tumor progression. Conclusions: We identified that METTL3 was upregulated in pancreatic cancer, leading to the upregulation of miR-196a, resulting in the downregulation of CPEB3, which promoted the pancreatic tumor progression. We first demonstrated that CPEB3 was a tumor suppressor gene in pancreatic cancer, and the METTL3 regulated miR-196a/CPEB3 axis may be a therapeutic target for pancreatic cancer therapy.

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COL11A1 is the Key Target Gene of MIST1 on Tumor Progression of Pancreatic Cancer

10.21203/rs.3.rs-793040/v1 ◽

2021 ◽

Author(s):

Yang Li ◽

Zhiqiang Liu ◽

Ying Sun ◽

Dianyun Ren ◽

Yongfeng Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Progression ◽

Cancer Cells ◽

Target Gene ◽

Animal Experiments ◽

Migration And Invasion ◽

Cancer Cell Growth ◽

Pancreatic Cancer Cells

Abstract Background: MIST1, a component of BHLH transcription factors, has been documented to be an important factor in tumor progression of pancreatic cancer, but the molecular mechanism is still unknown.Methods: COL11A1 was screened as a candidate key target gene of MIST1 in pancreatic cancer by ChIP -seq assay and verified by RT-PCR and Western Blotting on MIST1-overexpression pancreatic cancer cells. ChIP and dual-luciferase assays were performed to study the binding domain of MIST1 and COL11A1. Transwell invasion, wound healing, MTT, colony formation assays and animal experiments were performed to investigate the roles of COL11A1 expression on pancreatic cancer cells. Clinical data and TCGA datasets were used to evaluate the role of COL11A1 expression on prognosis for patients with pancreatic cancer.Results: MIST1 could bind to the promoter of COL11A1 as a negative transcription factor in pancreatic cancer. Overexpression of COL11A1 promotes pancreatic cancer cell growth, migration and invasion in vitro and in vivo. Expression of COL11A1 was upregulated in pancreatic cancer and positively correlated with a worse prognosis for patients with pancreatic cancer. Conclusions: These results demonstrated COL11A1 as a carcinogen in pancreatic cancer, and it acts as the key target gene of MIST1 on tumor progression of pancreatic cancer. COL11A1 can act as a potential therapeutic target of pancreatic cancer which is superior to MIST1.

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In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

Current Cancer Drug Targets ◽

10.2174/1568210204916170096 ◽

2010 ◽

Vol 999 (999) ◽

pp. 1-11

Author(s):

P. Ulivi ◽

C. Arienti ◽

W. Zoli ◽

M. Scarsella ◽

S. Carloni ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Antitumor Efficacy ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells

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Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo

Cancers ◽

10.3390/cancers13092017 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2017

Author(s):

Lital Sharvit ◽

Rinat Bar-Shalom ◽

Naiel Azzam ◽

Yaniv Yechiel ◽

Solomon Wasser ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Culture Liquid ◽

Human Pancreatic Cancer ◽

P53 Signaling ◽

Pancreatic Cancer Cells

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

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NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

Cell Death Discovery ◽

10.1038/s41420-021-00462-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Feng Guo ◽

Yingke Zhou ◽

Hui Guo ◽

Dianyun Ren ◽

Xin Jin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Transcriptional Activation ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells ◽

Gene Sets ◽

And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

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Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210201095613 ◽

2021 ◽

Vol 21 ◽

Author(s):

Huiming Chen ◽

Junfeng Zhao ◽

Ningning Jiang ◽

Zheng Wang ◽

Chang Liu

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Precancerous Lesions ◽

Clinical Specimen ◽

Ductal Adenocarcinoma ◽

Dependent Manner ◽

Pancreatic Cancer Cells ◽

Cancer Initiation

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear. Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.

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