Increased semaphorin 3c expression promotes tumor growth and metastasis in pancreatic ductal adenocarcinoma by activating the ERK1/2 signaling pathway

AbstractPancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens.

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Pancreatic Ductal Adenocarcinoma Mice Lacking Mucin 1 Have a Profound Defect in Tumor Growth and Metastasis

Cancer Research ◽

10.1158/0008-5472.can-10-4439 ◽

2011 ◽

Vol 71 (13) ◽

pp. 4432-4442 ◽

Cited By ~ 73

Author(s):

Dahlia M. Besmer ◽

Jennifer M. Curry ◽

Lopamudra D. Roy ◽

Teresa L. Tinder ◽

Mahnaz Sahraei ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Mucin 1 ◽

Tumor Growth And Metastasis

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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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OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.698302 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jinsheng Ding ◽

Hui Li ◽

Yang Liu ◽

Yongjie Xie ◽

Jie Yu ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathway ◽

Cell Lines ◽

Bioinformatics Analysis ◽

Gene Set Enrichment Analysis ◽

Ductal Adenocarcinoma ◽

Pdac Cell ◽

Coa Transferase

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with a five-year survival rate of less than 10%. Gemcitabine (GEM) is the most commonly used drug for PDAC chemotherapy. However, a vast majority of patients with PDAC develop resistance after GEM treatment.MethodsWe screened for GEM resistance genes through bioinformatics analysis. We used immunohistochemistry to analyze 3-oxoacid CoA-transferase 1 (OXCT1) expression in PDAC tissues. The survival data were analyzed using the Kaplan–Meier curve. The expression levels of the genes related to OXCT1 and the NF-κB signaling pathway were quantified using real−time quantitative PCR and western blot analyses. We performed flow cytometry to detect the apoptosis rate. Colony formation assay was performed to measure the cell proliferation levels. The cytotoxicity assays of cells were conducted using RTCA. The downstream pathway of OXCT1 was identified via the Gene Set Enrichment Analysis. Tumor growth response to GEM in vivo was also determined in mouse models.ResultsBioinformatics analysis revealed that OXCT1 is the key gene leading to GEM resistance. Patients with high OXCT1 expression exhibited short relapse-free survival under GEM treatment. OXCT1 overexpression in PDAC cell lines exerted inhibitory effect on apoptosis after GEM treatment. However, the down-regulation of OXCT1 showed the opposite effect. Blocking the NF-κB signaling pathway also reduced GEM resistance of PDAC cells. Tumor growth inhibition induced by GEM in vivo reduced after OXCT1 overexpression. Moreover, the effect of OXCT1 on GEM refractoriness in PDAC cell lines was reversed through using an NF-κB inhibitor.ConclusionOXCT1 promoted GEM resistance in PDAC via the NF-κB signaling pathway both in vivo and in vitro. Our results suggest that OXCT1 could be used as a potential therapeutic target for patients with PDAC.

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