Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11

Ungaro, Federica; Colombo, Piergiuseppe; Massimino, Luca; Ugolini, Giovanni Stefano; Correale, Carmen; Rasponi, Marco; Garlatti, Valentina; Rubbino, Federica; Tacconi, Carlotta; Scocco, Paola; Spinelli, Antonino; Carvello, Michele; Sacchi, Matteo; Spanò, Salvatore; Vetrano, Stefania; Malesci, Alberto; Peyrin–Biroulet, Laurent; Danese, Silvio; D’Alessio, Silvia

doi:10.1002/ijc.32286

Cited by 20 publications

(14 citation statements)

References 19 publications

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“…The gene encoding GDF11 has been mapped to a region of chromosome 12q13.2, which encodes a novel protein of 407 aa with a signal sequence for secretion, an RXXR proteolytic processing site, and a carboxyl terminal region containing a highly conserved pattern of cysteine residues. 42 , 43 , 44 , 45 Improving GDF11 expression has been shown to reduce ischemic stroke injury in mice. 46 , 47 Our results showed a negative regulation between miR-125b-5p and GDF11, indicating a potential neurotoxic role of miR-125b-5p.…”

Section: Discussionmentioning

confidence: 56%

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

Chen

Wang

Feng

et al. 2020

Molecular Therapy - Nucleic Acids

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Circular RNAs (circRNAs) are expressed at high levels in the brain and are involved in various central nervous system diseases. However, the potential role of circRNAs in ischemic stroke-associated neuronal injury remains largely unknown. Herein, we uncovered the function and underlying mechanism of the circRNA UCK2 (circUCK2) in ischemia stroke. The oxygen-glucose deprivation model in HT-22 cells was used to mimic ischemia stroke in vitro . Neuronal viability and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assays and TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) staining, respectively. Middle cerebral artery occlusion was conducted to evaluate the function of circUCK2 in mice. The levels of circUCK2 were significantly decreased in brain tissues from a mouse model of focal cerebral ischemia and reperfusion. Upregulated circUCK2 levels significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficits. circUCK2 reduced oxygen glucose deprivation (OGD)-induced cell apoptosis by regulating transforming growth factor β (TGF-β)/mothers against decapentaplegic homolog 3 (Smad3) signaling. Furthermore, circUCK2 functioned as an endogenous miR-125b-5p sponge to inhibit miR-125b-5p activity, resulting in an increase in growth differentiation factor 11 (GDF11) expression and a subsequent amelioration of neuronal injury. Consequently, these findings showed that the circUCK2/miR-125b-5p/GDF11 axis is an essential signaling pathway during ischemia stroke. Thus, the circRNA circUCK2 may serve as a potential target for novel treatment in patients with ischemic stroke.

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Section: Discussionmentioning

confidence: 56%

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

Chen

Wang

Feng

et al. 2020

Molecular Therapy - Nucleic Acids

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“…HILECs were isolated, as previously described [12], from inflamed ilea of n = 5 CD patients undergoing surgery, whose characteristics are listed in Table 1. Healthy HILECs were isolated from healthy resection margins of ilea of n = 5 patients undergoing surgery for colorectal cancer.…”

Section: Methodsmentioning

confidence: 99%

“…Healthy and CD HILECs were transduced with lentiviral particles, produced as previously described [12,13], carrying either Green Fluorescent Protein GFP (), GFP -tagged Arachidonate 12-Lipoxygenase, 12R Type (ALOX12B , OriGene Technologies, Inc., Rockville, MD, USA), GFP -tagged HtrA Serine Peptidase 4 (HTRA4, Origene), GFP -tagged Interleukin 20 Receptor Subunit Alpha (IL20RA , Origene), or GFP -tagged Signal Peptide, CUB Domain And EGF Like Domain Containing 2 (SCUBE2 , Origene Rockville, MD, USA) encoding sequences. A lentiviral vector construct encoding GFP -tagged BMP and activin membrane-bound inhibitor homolog (BAMBI ) was generated by PCR amplification of BAMBI cDNA with oligonucleotides carrying BamHI and MluI restriction sites (Primer Bamh1.forward 5′CCGGGATCCGCCACC ATGGACCGGCACAGCAGC 3′; Primer MluI.reverse 5′ CCG ACGCGT GGGGCCCAGAGGGGCC 3′).…”

Section: Methodsmentioning

confidence: 99%

mTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn’s Disease

Ungaro

Garlatti

Massimino

et al. 2019

Cells

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Crohn’s disease (CD) is a chronic inflammatory condition that can affect different portions of the gastrointestinal tract. Lymphatic drainage was demonstrated to be dysfunctional in CD pathogenesis, ultimately causing the failure of the resolution of intestinal inflammation. To investigate the molecular mechanisms underlying these dysfunctions, we isolated human intestinal lymphatic endothelial cells (HILECs) from surgical specimens of patients undergoing resection for complicated CD (CD HILEC) and from a disease-free margin of surgical specimens of patients undergoing resection for cancer (healthy HILEC). Both cell types underwent transcriptomic profiling, and their barrier functionality was tested using a transwell-based co-culture system between HILEC and lamina propria mononuclear cells (LPMCs). Results showed CD HILEC displayed a peculiar transcriptomic signature that highlighted mTOR signaling as an orchestrator of leukocyte trafficking through the lymphatic barrier of CD patients. Moreover, we demonstrated that LPMC transmigration through the lymphatic endothelium of patients with CD depends on the capability of mTOR to trigger interleukin 20 receptor subunit α (IL20RA)-mediated intracellular signaling. Conclusively, our study suggests that leukocyte trafficking through the intestinal lymphatic microvasculature can be controlled by modulating IL20RA, thus leading to the resolution of chronic inflammation in patients with CD.

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“…The impaired intestinal vascular function is also related to the pathogenesis of colorectal cancer. The lymphatic endothelium is affected by colorectal tumors to promote the tumor metastasis [109]. In contrast to the protective function of VEGF-C in IBD models, the same growth factor impaired the lymphatic vessel barrier and facilitated the entry and metastasis of colorectal tumors [110].…”

Section: Intestinal Vasculature In Diseasesmentioning

confidence: 99%

Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling

2020

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The human circulatory system is divided into two complementary and different systems, the cardiovascular and the lymphatic system. The cardiovascular system is mainly concerned with providing nutrients to the body via blood and transporting wastes away from the tissues to be released from the body. The lymphatic system focuses on the transport of fluid, cells, and lipid from interstitial tissue spaces to lymph nodes and, ultimately, to the cardiovascular system, as well as helps coordinate interstitial fluid and lipid homeostasis and immune responses. In addition to having distinct structures from each other, each system also has organ-specific variations throughout the body and both systems play important roles in maintaining homeostasis. Dysfunction of either system leads to devastating and potentially fatal diseases, warranting accurate models of both blood and lymphatic vessels for better studies. As these models also require physiological flow (luminal and interstitial), extracellular matrix conditions, dimensionality, chemotactic biochemical gradient, and stiffness, to better reflect in vivo, three dimensional (3D) microfluidic (on-a-chip) devices are promising platforms to model human physiology and pathology. In this review, we discuss the heterogeneity of both blood and lymphatic vessels, as well as current in vitro models. We, then, explore the organ-specific features of each system with examples in the gut and the brain and the implications of dysfunction of either vasculature in these organs. We close the review with discussions on current in vitro models for specific diseases with an emphasis on on-chip techniques.

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Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11

Cited by 20 publications

References 19 publications

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

mTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn’s Disease

Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling

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