Tumor Necrosis Factor‐α Increases Claudin‐1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes

Amoozadeh, Yasaman; Dan, Qinghong; Anwer, Shaista; Huang, Hsiao Han; Barbieri, Vanessa; Waheed, Faiza; Maishan, Mazharul; Szászi, Katalin

doi:10.1002/jcp.25736

Cited by 16 publications

(12 citation statements)

References 68 publications

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“…MAPK/JNK signalling pathway was reported to be involved in regulating EMT. Phosphorylated JNK may also affect tight junction (TJ) through regulation of claudins . Our qRT‐PCR and WB results further confirmed this phenomenon.…”

Section: Discussionsupporting

confidence: 77%

BHLHE41 suppresses MCF‐7 cell invasion via MAPK/JNK pathway

Zhang

Zheng

Wang

et al. 2020

J Cellular Molecular Medi

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| 4001 wileyonlinelibrary.com/journal/jcmm | INTRODUC TI ONBasic helix-loop-helix family member e41 (BHLHE41, also known as SHARP1, DEC2 and BHLHB3) is mapped to human chromosome 12p12.1. It serves an important role in regulating cell differentiation, maintaining circadian rhythm, apoptosis, hypoxia and immune response. [1][2][3][4][5][6][7][8][9][10][11] The major functions of BHLHE41 are divided into two categories: circadian and non-circadian regulation. For the former, BHLHE41 protein re-enters the nucleus after transcription and translation and competes with CLOCK-BMAL1 heterodimer for E-Box element binding (through competitive inhibition). BHLHE41 functions as a suppressor of circadian rhythm regulation in this process. 11,12 For non-circadian regulation, BHLHE41 is implicated in multiple other pathways, such as BCR, notch, hypoxia, ERK/NF-kappaB and PI3K/Akt pathways. 3,6,8,[13][14][15] Dysregulation of BHLHE41 transcription levels has been characterized as a marker of the progression of several cancers. 8,[16][17][18][19][20][21][22][23] Abstract Deregulation of the basic helix-loop-helix family member e41 (BHLHE41) has been characterized as a marker of progression of several cancers. In this study, we aimed to explore the mechanism by which BHLHE41 regulates the invasion of breast cancer cells. BHLHE41 suppresses, whereas the silencing of BHLHE41 promotes tumour invasion of both MCF-7 and MDA-MB-231 cells. Meanwhile, BHLHE41 down-regulated the transcription and translation of SNAI1, SNAI2, VIM and CDH2, and up-regulated those of CLDN1, CLDN4 and CDH1. Reporter assay indicated that silencing of BHLHE41 dramatically activated the MAPK/JNK signalling pathway in MCF-7 cell line and the hypoxia signalling pathway in MDA-MB-231 cell line. Furthermore, silencing of BHLHE41 activated the MAPK/JNK signalling pathway by up-regulating phosphorylated JNK and failed to affect the expression of HIF-1 alpha in MCF-7 cells. After blocking the MAPK/JNK signalling pathway by specific inhibitor SP600125, silencing of BHLHE41 failed to promote tumour cell invasion. These results suggest that BHLHE41 facilitates MCF-7 cell invasion mainly via the activation of MAPK/ JNK signalling pathway. In conclusion, although BHLHE41 suppresses tumour invasion in MCF-7 and MDA-MB-231 cell lines, the specific regulatory mechanisms may be different. K E Y W O R D S BHLHE41, breast cancer, invasion, JNK signalling pathway, tight junction How to cite this article: Zhang D, Zheng Q, Wang C, Zhao N, Liu Y, Wang E. BHLHE41 suppresses MCF-7 cell invasion via MAPK/JNK pathway.

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Section: Discussionsupporting

confidence: 77%

BHLHE41 suppresses MCF‐7 cell invasion via MAPK/JNK pathway

Zhang

Zheng

Wang

et al. 2020

J Cellular Molecular Medi

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“…Cldn1, Cldn3 and Cldn4 were classified to pore‐sealing Cldns in Cldn family. They fucntion as a barier to stop water, ions and molecules from passing through, which would decrease permeability of the epithelium (Khan and Asif, 2015; Amoozadeh et al , 2017). Therefore, the higher expression of Cldn1 and Cldn3 might stop saliva components passing through the acinar epithelium and reduce salivary secretion in diabetes SMGs.…”

Section: Discussionmentioning

confidence: 99%

“…Our study revealed that Cldn1 and Cldn3 were upregulated, while Cldn10 and Ocln were downregulated in db/db mice. Cldn10 was reported to be pore‐forming claudins, which can increase TJ permeability (Khan and Asif, 2015; Amoozadeh et al , 2017). Therefore, lower Cldn10 level might reduce TJ permeability and inhibit salivation through the paracellular pathway.…”

Section: Discussionmentioning

confidence: 99%

Disruption of tight junctions contributes to hyposalivation of salivary glands in a mouse model of type 2 diabetes

et al. 2020

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Tight junction (TJ) plays an important role in regulating paracellular fluid transport in salivary glands; however, little is known about the involvement of TJs in diabetes salivary glands. This study aimed to investigate the alterations of TJs and their possible contribution in diabetes‐induced hyposalivation. Here, we observed that the morphologies of submandibular glands (SMGs) were impaired, characterized by enlarged acini accumulation with giant secretory granules, which were significantly reduced in atrophic ducts in SMGs of db/db mice, a spontaneous model of type‐2 diabetes. However, the secretory granules were increased and scattered in the acini of diabetes parotid glands (PGs). Other ultrastructural damages including swollen mitochondria, expansive endoplasmic reticulum, and autophagosomes were observed in the diabetes group. The levels of TJ proteins including claudin‐1 (Cldn1) and claudin‐3 (Cldn3) were increased, whereas those of claudin‐4 (Cldn4), occludin (Ocln), and zonula occludens‐1 (ZO‐1) were decreased in SMGs of db/db mice. Higher Cldn1 and Cldn3 and lower claudin‐10 (Cldn10) and Ocln levels were observed in PGs of diabetes mice. Taken together, the structures of SMGs and PGs were impaired in diabetes mice, and the disruption of TJ integrity in both SMGs and PGs may contribute to diabetes‐induced hyposalivation.

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“…The following antibodies against tight junction molecules were from Thermo/Invitrogen and have been validated earlier (19,69,90): claudin-2: monoclonal mouse antibody (catalog no. 325600) (used for Western blotting) and polyclonal rabbit antibody (catalog no.…”

Section: Materials and Antibodiesmentioning

confidence: 99%

Claudin-2 suppresses GEF-H1, RHOA, and MRTF, thereby impacting proliferation and profibrotic phenotype of tubular cells

Dan

Shi

Rabani

et al. 2019

Journal of Biological Chemistry

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The tight junctional pore-forming protein claudin-2 (CLDN-2) mediates paracellular Na ؉ and water transport in leaky epithelia and alters cancer cell proliferation. Previously, we reported that tumor necrosis factor-␣ time-dependently alters CLDN-2 expression in tubular epithelial cells. Here, we found a similar expression pattern in a mouse kidney injury model (unilateral ureteral obstruction), consisting of an initial increase followed by a drop in CLDN-2 protein expression. CLDN-2 silencing in LLC-PK 1 tubular cells induced activation and phosphorylation of guanine nucleotide exchange factor H1 (GEF-H1), leading to Ras homolog family member A (RHOA) activation. Silencing of other claudins had no such effects, and re-expression of an siRNA-resistant CLDN-2 prevented RHOA activation, indicating specific effects of CLDN-2 on RHOA. Moreover, kidneys from CLDN-2 knockout mice had elevated levels of active RHOA. Of note, CLDN-2 silencing reduced LLC-PK1 cell proliferation and elevated expression of cyclin-dependent kinase inhibitor P27 (P27KIP1) in a GEF-H1/RHOA-dependent manner. P27KIP1 silencing abrogated the effects of CLDN-2 depletion on proliferation. CLDN-2 loss also activated myocardin-related transcription factor (MRTF), a fibrogenic RHOA effector, and elevated expression of connective tissue growth factor and smooth muscle actin. Finally, CLDN-2 downregulation contributed to RHOA activation and smooth muscle actin expression induced by prolonged tumor necrosis factor-␣ treatment, because they were mitigated by re-expression of CLDN-2. Our results indicate that CLDN-2 suppresses GEF-H1/RHOA. CLDN-2 down-regulation, for example, by inflammation, can reduce proliferation and promote MRTF activation through RHOA. These findings suggest that the initial CLDN-2 elevation might aid epithelial regeneration, and CLDN-2 loss could contribute to fibrotic reprogramming.

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Tumor Necrosis Factor‐α Increases Claudin‐1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes

Cited by 16 publications

References 68 publications

BHLHE41 suppresses MCF‐7 cell invasion via MAPK/JNK pathway

BHLHE41 suppresses MCF‐7 cell invasion via MAPK/JNK pathway

Disruption of tight junctions contributes to hyposalivation of salivary glands in a mouse model of type 2 diabetes

Claudin-2 suppresses GEF-H1, RHOA, and MRTF, thereby impacting proliferation and profibrotic phenotype of tubular cells

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