Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Zhou, Baosen; Flodby, Per; Luo, Jiao; Castillo, Dan R.; Liu, Yixin; Yu, Fa‐Xing; McConnell, Alicia M.; Varghese, Bino; Li, Guanglei; Chimge, Nyam-Osor; Sunohara, Mitsuhiro; Koss, Michael N.; Elatre, Wafaa; Conti, Peter; Liebler, Janice M.; Yang, Chengli; Marconett, Crystal N.; Laird-Offringa, Ite A.; Minoo, Parviz; Guan, Kun‐Liang; Stripp, Barry R.; Crandall, Edward D.; Borok, Zea

doi:10.1172/jci90429

Cited by 129 publications

(128 citation statements)

References 85 publications

(96 reference statements)

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“…Furthermore, confocal images show the proportion of nuclear YAP and TAZ decreases in Dox-treated cells (Figure 5C–D) and accordingly, qRT-PCR analysis indicates 3–5 fold inhibition of YAP/TAZ target gene expression by CLDN18.1 (Figure 5E). These results are consistent with our previous in vivo data indicating negative regulation of YAP by CLDN18 (18). We then tested by siRNA silencing the potential roles of YAP and TAZ in regulating AKT.…”

Section: Resultssupporting

confidence: 94%

“…In contrast to CLDN18.1 , there was no significant inverse association between CLDN18.2 expression (mean = 1132 ± 3998) and patient survival in the TCGA LuAd cohort (Supplemental Figure 1D). These results validate a tumor suppressor role for CLDN18.1 in human LuAd consistent with the development of such tumors in the Cldn18 −/− mouse model (18). …”

Section: Resultssupporting

confidence: 82%

“…Protein extracts (10–60 μg) were resolved by SDS-PAGE and transferred to PVDF membranes (Bio-Rad; #162-0177) as previously described (36). Sources of antibodies and their dilution factors were as follows: anti-CLDN18 (Life Technologies, Grand Island, NY; #700178; 1:500), anti-lamin A/C (Santa Cruz Biotechnology, Santa Cruz, CA; #sc20681; 1:2000), anti-α-tubulin (Sigma-Aldrich, #6-11B-1; 1:5000), anti-β-actin (Abcam, Cambridge, MA; #ab8227; 1:5000) and anti-GAPDH (Ambion, Foster City, CA; #AM4300; 1:2000).…”

Section: Methodsmentioning

confidence: 99%

“…Whereas numerous studies have focused on ectopic expression of CLDN18.2 , investigation of CLDN18.1 in cancer has been limited (15,16). Using Cldn18 −/− mice, in which both Cldn18.1 and Cldn18.2 isoforms are globally deleted, we recently assigned a role for CLDN18 in regulating not only epithelial permeability and ion transport, but also proliferation of lung alveolar epithelial type II (AT2) cells, organ size and tumorigenicity (17,18). In the present study, we address in vivo and in vitro the contributions of CLDN18.1 to the malignant phenotype of human LuAd.…”

Section: Introductionmentioning

confidence: 99%

“…YAP/TAZ activity is regulated in both Hippo kinase-dependent and -independent manners (25,31). We have recently reported that CLDN18 interacts with YAP in murine AT2 cells, resulting in nuclear exclusion and downregulation of YAP target genes (18). …”

Section: Introductionmentioning

confidence: 99%

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CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro

Luo

Chimge

Zhou

et al. 2018

Intl Journal of Cancer

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Claudins are a family of transmembrane proteins integral to the structure and function of tight junctions (TJ). Disruption of TJ and alterations in claudin expression are important features of invasive and metastatic cancer cells. Expression of CLDN18.1, the lung-specific isoform of CLDN18, is markedly decreased in lung adenocarcinoma (LuAd). Furthermore, we recently observed that aged Cldn18−/− mice have increased propensity to develop LuAd. We now demonstrate that CLDN18.1 expression correlates inversely with promoter methylation and with LuAd patient mortality. In addition, when restored in LuAd cells that have lost expression, CLDN18.1 markedly attenuates malignant properties including xenograft tumor growth in vivo as well as cell proliferation, migration, invasion and anchorage-independent colony formation in vitro. Based on high throughput analyses of Cldn18−/− murine lung alveolar epithelial type II cells, as well as CLDN18.1-repleted human LuAd cells, we hypothesized and subsequently confirmed by Western analysis that CLDN18.1 inhibits insulin-like growth factor-1 receptor (IGF-1R) and AKT phosphorylation. Consistent with recent data in Cldn18−/− knockout mice, expression of CLDN18.1 in human LuAd cells also decreased expression of transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) and their target genes, contributing to its tumor suppressor activity. Moreover, analysis of LuAd cells in which YAP and/or TAZ are silenced with siRNA suggests that inhibition of TAZ, and possibly YAP, is also involved in CLDN18.1-mediated AKT inactivation. Taken together, these data indicate a tumor suppressor role for CLDN18.1 in LuAd mediated by a regulatory network that encompasses YAP/TAZ, IGF-1R and AKT signaling.

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Section: Resultssupporting

confidence: 94%

Section: Resultssupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro

Luo

Chimge

Zhou

et al. 2018

Intl Journal of Cancer

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A Monoclonal Human Alveolar Epithelial Cell Line (“Arlo”) with Pronounced Barrier Function for Studying Drug Permeability and Viral Infections

et al. 2023

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In the development of orally inhaled drug products preclinical animal models regularly fail to predict pharmacological as well as toxicological responses in humans. Models based on human cells and tissues are potential alternatives to animal experimentation allowing for the isolation of essential processes of human biology and making them accessible in vitro. Here, the generation of a novel monoclonal cell line "Arlo," derived from the polyclonal human alveolar epithelium lentivirus immortalized cell line hAELVi via single-cell printing, and its characterization as a model for the human alveolar epithelium as well as a building block for future complex in vitro models is described. "Arlo" is systematically compared in vitro to primary human alveolar epithelial cells (hAEpCs) as well as to the polyclonal hAELVi cell line. "Arlo" cells show enhanced barrier properties with high transepithelial electrical resistance (TEER) of ≈3000 Ω cm 2 and a potential difference (PD) of ≈30 mV under air-liquid interface (ALI) conditions, that can be modulated. The cells grow in a polarized monolayer and express genes relevant to barrier integrity as well as homeostasis as is observed in hAEpCs. Successful productive infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a proof-of-principle study offers an additional, attractive application of "Arlo" beyond biopharmaceutical experimentation.

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Immune landscape and a promising immune prognostic model associated with TP53 in early‐stage lung adenocarcinoma

Xiang

Wei

2020

Cancer Medicine

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Purpose TP53 mutation, one of the most frequent mutations in early‐stage lung adenocarcinoma (LUAD), triggers a series of alterations in the immune landscape, progression, and clinical outcome of early‐stage LUAD. Our study was designed to unravel the effects of TP53 mutation on the immunophenotype of early‐stage LUAD and formulate a TP53‐associated immune prognostic model (IPM) that can estimate prognosis in early‐stage LUAD patients. Materials and methods Immune‐associated differentially expressed genes (DEGs) between TP53 mutated (TP53MUT) and TP53 wild‐type (TP53WT) early‐stage LUAD were comprehensively analyzed. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) analysis identified the prognostic immune‐associated DEGs. We constructed and validated an IPM based on the TCGA and a meta‐GEO composed of GSE72094, GSE42127, and GSE31210, respectively. The CIBERSORT algorithm was analyzed for assessing the percentage of immune cell types. A nomogram model was established for clinical application. Results TP53 mutation occurred in approximately 50.00% of LUAD patients, stimulating a weakened immune response in early‐stage LUAD. Sixty‐seven immune‐associated DEGs were determined between TP53WT and TP53MUT cohort. An IPM consisting of two prognostic immune‐associated DEGs (risk score = 0.098 * ENTPD2 expression + 0.168 * MIF expression) was developed through 397 cases in the TCGA and further validated based on 623 patients in a meta‐GEO. The IPM stratified patients into low or high risk of undesirable survival and was identified as an independent prognostic indicator in multivariate analysis (HR = 2.09, 95% CI: 1.43–3.06, p < 0.001). Increased expressions of PD‐L1, CTLA‐4, and TIGIT were revealed in the high‐risk group. Prognostic nomogram incorporating the IPM and other clinicopathological parameters (TNM stage and age) achieved optimal predictive accuracy and clinical utility. Conclusion The IPM based on TP53 status is a reliable and robust immune signature to identify early‐stage LUAD patients with high risk of unfavorable survival.

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Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Cited by 129 publications

References 85 publications

CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro

CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro

A Monoclonal Human Alveolar Epithelial Cell Line (“Arlo”) with Pronounced Barrier Function for Studying Drug Permeability and Viral Infections

Immune landscape and a promising immune prognostic model associated with TP53 in early‐stage lung adenocarcinoma

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