CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice

Nguyen, Hang Thi Thu; Dalmasso, Guillaume; Törkvist, Leif; Halfvarson, Jonas; Yan, Yutao; Laroui, Hamed; Shmerling, D. H.; Tallone, Tiziano; D’Amato, Mauro; Sitaraman, Shanthi V.; Merlin, Didier

doi:10.1172/jci44631

Cited by 112 publications

(150 citation statements)

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“…8 Founder C57BL/6J male mice heterozygous for the Apc Min allele (Apc Min/ þ ) were purchased from the Jackson Laboratory. Tg mice were congenically rebred to C57Bl/6 (Jackson Laboratories) for eight generations.…”

Section: Methodsmentioning

confidence: 99%

“…8 As both cell proliferation and survival contribute to tumor growth, we investigated these properties in Tg/Apc Min/ þ mice in comparison with Apc Min/ þ animals to understand the mechanism underlying the effect of IEC-specific CD98 overexpression on tumor development. Immunohistological staining for Ki67 revealed a significant increase in the number of Ki67-positive epithelia in Tg/ Apc Min/ þ mice compared with Apc Min/ þ animals, in both tumor and non-tumor regions (Figure 3a).…”

Section: Western Blotmentioning

confidence: 99%

“…26 We recently showed that IEC-specific CD98 overexpression increases activation of MEK-ERK signaling pathway. 8 Therefore, we examined the levels of phospho-ERK in Apc Min/ þ and Tg/Apc Min/ þ mice. Figure 5d shows that, compared with Apc Min/ þ mice, intestinal lysates of Tg/Apc Min/ þ animals exhibited a marked increase in phospho-ERK level.…”

Section: Western Blotmentioning

confidence: 99%

“…[4][5][6][7] Recently, we generated both gain-and loss-of-function mouse models featuring genetic manipulation of CD98 expression specifically in intestinal epithelial cells (IECs), and explored the roles of CD98 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. 8 The adenomatous polyposis coli (APC) gene is critical for initiation of colorectal cancer (CRC), one of the most common malignancies worldwide. 9 APC is mutated in 495% of familial adenomatous polyposis patients, and in 80% of those with sporadic CRC.…”

mentioning

confidence: 99%

“…14 In the nucleus, b-catenin forms a complex with T-cell factor (TCF); this complex in turn activates oncogenes including c-myc 15 and cyclin D1. 16,17 In the present study, we used two genetically manipulated mouse strains 8 that exhibit either IEC-specific CD98 overexpression or downregulation. We investigated the role shown by CD98, and its mechanism(s) of action, in intestinal tumorigenesis in Apc Min/ þ mice.…”

mentioning

confidence: 99%

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Intestinal epithelial cell-specific CD98 expression regulates tumorigenesis in ApcMin/+ mice

Nguyen

Dalmasso

Yan

et al. 2012

Laboratory Investigation

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The transmembrane glycoprotein CD98 regulates integrin signaling that in turn controls cell proliferation and survival. CD98 expression is upregulated in various carcinomas, including colorectal cancer. Recently, by generating gain-and loss-of-function mouse models featuring genetic manipulation of CD98 expression specifically in intestinal epithelial cells (IECs), we have explored the crucial role of CD98 in the regulation of intestinal homeostasis and inflammation-associated tumorigenesis. In the present study, we investigated the contribution of CD98 to intestinal tumorigenesis in Apc Min/ þ mice and the underlying mechanism of action. Mice featuring IEC-specific CD98 overexpression (Tg animals) were crossed with Apc Min/ þ mice, and the characteristics of intestinal adenoma formation were assessed. Compared with Apc Min/ þ mice, Tg/Apc Min/ þ animals exhibited increases in both intestinal tumor incidence and tumor size; these parameters correlated with enhanced proliferation and decreased apoptosis of IECs. IEC-specific CD98 overexpression resulted in increased synthesis of the oncogenic proteins c-myc and cyclin-D1 in Apc Min/ þ mice, independently of the Wnt-APC-bcatenin pathway, suggesting the implication of CD98 overexpression-mediated Erk activation. IEC-specific CD98 overexpression enhanced the production of proinflammatory cytokines and chemokines that are crucial for tumorigenesis. We validated our results in mice exhibiting IEC-specific CD98 downregulation (CD98 flox/ þ VillinCre animals). IEC-specific CD98 downregulation efficiently attenuated tumor incidence and growth in Apc Min/ þ mice. The reduction of intestinal tumorigenesis upon IEC-specific CD98 downregulation was caused by the attenuation of IEC proliferation and cytokine/ chemokine production. In conclusion, we show that CD98 exerts an oncogenic activity in terms of intestinal tumorigenesis, via an ability to regulate tumor growth and survival.

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Section: Methodsmentioning

confidence: 99%

Section: Western Blotmentioning

confidence: 99%

Section: Western Blotmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Intestinal epithelial cell-specific CD98 expression regulates tumorigenesis in ApcMin/+ mice

Nguyen

Dalmasso

Yan

et al. 2012

Laboratory Investigation

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Evolving Experimental Platforms to Evaluate Ulcerative Colitis

et al. 2022

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tissue thus altering tissue integrity, anatomy, and physiology subsequently affecting the overall health-related quality of life (HRQoL) of afflicted individuals. [1][2][3] It is estimated that the lifetime financial loss associated with the typical UC patient can be greater than $1 million/patient to cover direct and indirect medical expenses including treatment, hospitalizations, and general medical care. [3][4][5][6][7] As an example, vedolizumab and adalimumab treatment for UC had total direct medical costs of $100 022 and $151 133, respectively, per patient. [8] This number varies greatly depending upon the severity of the disease with a greater expense attributed to those exhibiting a poor clinical disposition. At the domestic level, the total cost to treat UC is estimated to be between $4-14 billion per year which seems to rise on an annual basis. [3,6,7] The specific etiological basis regarding the initiation and progression of UC is currently unknown. Physical manifestations of severe UC take the form of ulcerations affecting the mucosal lining, specifically along the length of the affected large intestine and rectum as depicted in Figure 1. These lesions contain an overabundant accumulation of innate and adaptive immune cells, including T cells, that promote an inflammatory environment Ulcerative colitis (UC) is a multifactorial disease defined by chronic intestinal inflammation with idiopathic origins. It has a predilection to affect the mucosal lining of the large intestines and rectum. Management of UC depends upon numerous factors that include disease pathogenesis and severity that are maintained via medical or surgical means. Chronic inflammation that is left untreated or managed poorly from a clinical stance can result in intestinal ulceration accompanied by resulting physiological dysfunction. End-stage UC is mediated by surgical intervention with the resection of diseased tissue. This can lead to numerous health-related quality of life issues but is considered a curative approach. Regimens to treat UC are ever evolving and find their basis within various platforms to evaluate and treat UC. Numerous modeling systems have been examined to delineate potential mechanisms of action. However, UC is a heterogenous disease spanning unknown genetic origins coupled with environmental factors that can influence disease outcomes and related treatment procedures. Unfortunately, there is no one-size-fits-all model to fully assess all facets of UC. Within the context of this review article, the utility of various approaches that have been employed to gain insight into different aspects of UC will be investigated.

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Macrophage‐Derived Extracellular Vesicles‐Coated Palladium Nanoformulations Modulate Inflammatory and Immune Homeostasis for Targeting Therapy of Ulcerative Colitis

Cheng,

Zhang,

et al. 2023

Advanced Science

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Ulcerative colitis (UC) is a chronic inflammatory bowel disease mainly involving the colon and rectum, which features recurrent mucosal inflammation. The excessive production of reactive oxygen species (ROS) is a trigger for pathological changes such as cell apoptosis and disordered immune microenvironments, which are crucial for the progression of UC and can be a promising therapeutic target. Nowadays, the development of targeted therapeutic strategies for UC is still in its infancy. Thus, developing effective therapies based on ROS scavenging and elucidating their molecular pathways are urgently needed. Herein, a biomimetic nanoformulation (Pd@M) with cubic palladium (Pd) as the core and macrophage‐derived extracellular vesicles (MEVs) as the shell is synthesized for the treatment of UC. These Pd@M nanoformulations exhibit multienzyme‐like activities for effective ROS scavenging, excellent targeting ability as well as good biocompatibility. It is verified that Pd@M can regulate the polarization state of macrophages by inhibiting glycolysis, and decrease neutrophil infiltration and recruitment. In this way, the colonic inflammatory and immune microenvironment is remodeled, and apoptosis is prevented, ultimately improving colonic mucosal barrier function and alleviating colitis in the mouse model. This finding provides a promising alternative option for the treatment of UC patients.

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CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice

Cited by 112 publications

References 39 publications

Intestinal epithelial cell-specific CD98 expression regulates tumorigenesis in ApcMin/+ mice

Intestinal epithelial cell-specific CD98 expression regulates tumorigenesis in ApcMin/+ mice

Evolving Experimental Platforms to Evaluate Ulcerative Colitis

Macrophage‐Derived Extracellular Vesicles‐Coated Palladium Nanoformulations Modulate Inflammatory and Immune Homeostasis for Targeting Therapy of Ulcerative Colitis

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