LRG-1 promotes pancreatic cancer growth and metastasis via modulation of the EGFR/p38 signaling

Xie, Zhibo; Zhang, Yifan; Jin, Chen; Mao, Yishen; Fu, Deliang

doi:10.1186/s13046-019-1088-0

Cited by 56 publications

(42 citation statements)

References 52 publications

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“…We also demonstrated a promoting role of LRG1 in the expression of cell-cycle marker cyclin D1. These results are in line with previous studies that LRG1 increases proliferation of different epithelial-derived cancer cells, such as colorectal cancer cells ( 40 ), pancreatic ductal adenocarcinoma ( 17 ), non-small-cell lung cancer cells ( 41 ), and gastric cancer cells ( 15 ). Consistent with the previous report ( 21 ), we showed that LRG1 overexpression and knockdown affect keratinocyte migration.…”

Section: Discussionsupporting

confidence: 93%

“…Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that was previously reported to regulate pathological neovascularization in the eye by switching the angiostatic TGFβ1-Smad2/3 signaling toward the proangiogenic TGFβ1-Smad1/5/8 signaling in endothelial cells ( 11 ). Besides its role in ocular angiogenesis, LRG1 is intimately associated with many inflammatory and autoimmune conditions ( 12 – 14 ) and tumor malignancy ( 15 – 17 ), which shares fundamental molecular mechanisms with chronic wound healing ( 18 ). Recently, elevated serum LRG1 levels were reported in patients with diabetes with peripheral arterial disease ( 19 ), a major risk factor for diabetic foot ulcers (DFU) ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

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A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions

et al. 2020

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Delayed wound healing is commonly associated with diabetes. It may lead to amputation and death if not treated in a timely fashion. Limited treatments are available partially due to the poor understanding of the complex disease pathophysiology. Here, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in normal and diabetic wound healing. First, our data showed that LRG1 was significantly increased at the inflammation stage of murine wound healing, and bone marrow–derived cells served as a major source of LRG1. LRG1 deletion causes impaired immune cell infiltration, reepithelialization, and angiogenesis. As a consequence, there is a significant delay in wound closure. On the other hand, LRG1 was markedly induced in diabetic wounds in both humans and mice. LRG1-deficient mice were resistant to diabetes-induced delay in wound repair. We further demonstrated that this could be explained by the mitigation of increased neutrophil extracellular traps (NETs) in diabetic wounds. Mechanistically, LRG1 mediates NETosis in an Akt-dependent manner through TGFβ type I receptor kinase ALK5. Taken together, our studies demonstrated that LRG1 derived from bone marrow cells is required for normal wound healing, revealing a physiological role for this glycoprotein, but that excess LRG1 expression in diabetes is pathogenic and contributes to chronic wound formation.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions

et al. 2020

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“…When EGFR triggers by growth factors, it mainly regulates cell proliferation and other biological processes through activation of downstream signaling pathways [ 20 ]. EGFR activation-associated downstream signaling pathway mainly includes ERK [ 21 ], p38 [ 22 ] and AKT [ 23 ] signaling pathways, which have to explore on the potential functional mechanism by which Eppk1 mediates cell proliferation of CC. Besides, KLF5 widely expresses in different tissues and plays a higher role in cell proliferation than in cell differentiation [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

KLF5-mediated Eppk1 expression promotes cell proliferation in cervical cancer via the p38 signaling pathway

Pan

Chang

et al. 2021

BMC Cancer

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Background Epiplakin1 (Eppk1) is part of epidermal growth factor (EGF) signal and takes part in reorganization of cytoskeleton and cell proliferation. However, the role of Eppk1 in cervical cancer (CC) remains unknown. Methods To express Eppk1 and KLF5 and their correlation, we used RNA-sequence, RT-qPCR, TCGA database and immunofluorescence staining in vitro and in different pathological cervical tissues. In CC cell lines, we tested adenovirus-mediated over expression or knockdown of KLF5 and siRNA-mediated knockdown of Eppk1 and a suiting assessment of cell proliferation and cell signaling by western blot and CCK8 tests. We studied the mechanism by which KLF5 regulates Eppk1 expression by reporter gene test and chromatin immunoprecipitation test. Results Eppk1 expression promoted in CC tissues and cell lines compared with increased KLF5 expression. The results of immunofluorescence staining further showed the increased co-expression of Eppk1 and KLF5 correlated substantially with tumorigenesis in cervical tissues. Overexpression of KLF5 significantly increased Eppk1 expression at transcription and translation levels. Conversely, the knockdown of KLF5 by siRNA against KLF5 decreased Eppk1 expression. Mechanically, KLF5 activated Eppk1 transcription by direct binding to the Eppk1 promoter. Gain- and loss-of-function experiments reported that KLF5 promoted cell proliferation in Hela partly dependent on Eppk1 upregulation. Besides, KLF5-mediated activation of p38 signaling significantly decreased after Eppk1 knockdown compared with decline of proliferation, suggesting that Eppk1 lies upstream of p38 signaling affecting cell proliferation. Finally, Eppk1 expression is positively correlated with tumor size in clinicopathological features of CC. Conclusions Eppk1 may be an effective therapeutic target for affecting p38 signaling pathway and cell proliferation in cervical cancer.

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“…EGFR activation-associated downstream signaling pathway mainly includes ERK [21], p38 [22] and AKT [23] signalings, which need to explored the potential functional mechanism by which Eppk1 mediates cell proliferation of CC. Furthermore, KLF5 is widely expressed in different tissues and plays a higher role in cell proliferation than in cell differentiation [24].…”

Section: Discussionmentioning

confidence: 99%

KLF5-mediated EPPK1 Expression Promotes Cell Proliferation in Cervical Cancer via the P38 Signaling Pathway

Pan

Liu

Chang

et al. 2020

Preprint

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Abstract Background: Epiplakin1 (Eppk1) is part of the EGF signal and is involved in cytoskeleton reorganization and cell proliferation. However, the role of Eppk1 in cervical cancer remains unknown. Methods: The expression of Eppk1 and KLF5 as well as their correlation were assessed by RNA-seq, qRT-PCR, TCGA database and immunofluorescence staining. In CC cell lines, adenovirus-mediated overexpression or knockdown of KLF5 and Eppk1 as well as corresponding assessment of cell proliferation and signaling were determined by western blot and CCK8 experiments. Assays of lucifase reporter gene and CHIP were used to investigate mechanism between KLF5 and Eppk1. Results: Eppk1 expression was markedly in CC tissues and cell lines companied by KLF5 upregulation. The results of immunofluorescence staining further showed that the increased expression of Eppk1 and KLF5 correlated with progression of cervical tumorigenesis. Overexpression of KLF5 significantly increased Eppk1 expression at transcription and translation levels. Conversely, the knockdown of KLF5 by siRNA against KLF5 decreased Eppk1 expression. Mechanical studies showed that KLF5 activated Eppk1 transcription by direct binding to the Eppk1 promoter. Gain- and loss-of-function experiments showed that KLF5 promoted cell proliferation in Hela by upregulating Eppk1 expression. Moreover, KLF5-mediated the activation of EGFR and p38 signaling significantly decreased after Eppk1 knockdown companied with reduction of proliferating activity, suggesting that Eppk1 lies upstream of p38 signaling affecting cell proliferation in CC. Finally, the expression of Eppk1 positively correlated with tumor size. Conclusions: Eppk1 may be an effective therapeutic target on affecting EGFR-associated p38 signaling pathway and cell proliferation in cervical cancer.

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LRG-1 promotes pancreatic cancer growth and metastasis via modulation of the EGFR/p38 signaling

Cited by 56 publications

References 52 publications

A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions

A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions

KLF5-mediated Eppk1 expression promotes cell proliferation in cervical cancer via the p38 signaling pathway

KLF5-mediated EPPK1 Expression Promotes Cell Proliferation in Cervical Cancer via the P38 Signaling Pathway

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