CLDN1 induces autophagy to promote proliferation and metastasis of esophageal squamous carcinoma through AMPK/STAT1/ULK1 signaling

Wu, Jian; Gao, Feng; Xu, Tao; Li, Jun; Hu, Zhi; Wang, Chao; Long, Yang; He, Xuemei; Deng, Xin; Ren, Dazhong; Zhou, Biao; Dai, Tianyang

doi:10.1002/jcp.29133

Cited by 37 publications

(28 citation statements)

References 37 publications

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“…In addition, other studies have suggested that STAT1 promotes tumor growth by inhibiting tumor immune surveillance and by promoting tumor resistance against chemotherapy and irradiation. For example, activation of STAT1 by the cancer-up-regulated gene 2 enhances metastasis and drug resistance in colon cancer cells (42)(43)(44). Taken together, these data suggest that JAK-STAT activity is likely cancer type-dependent, especially in CRC.…”

Section: Discussionmentioning

confidence: 83%

Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2‑STAT1‑Mcl‑1 axis

Wang

Zhang

et al. 2021

Oncol Lett

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Under pathological conditions, the Janus kinase (JAK)/STAT signaling pathway can regulate the proliferation, differentiation and migration of tumor cells, including colorectal cancer (CRC). CRC is the third major types of cancer among males and the second among females worldwide. In China, CRC is the fifth common cancer among both males and females. Western blotting, flow cytometry, RNA interference, immunoprecipitation, xenografts models, and immunohistochemical staining were carried out to evaluate the possible mechanisms of acton of ruxolitinib. The present data suggested that ruxolitinib can suppress CRC cell proliferation by inducing apoptosis. Firstly, JAK1/2-STAT1 was identified as the target of ruxolitinib. Then, ruxolitinib downregulated myeloid cell leukemia-1 (Mcl-1) mRNA level and decreased its protein level, which enabled Bak to trigger CRC apoptosis. Furthermore, ruxolitinib exerted potent activity against CRC xenograft growth in vivo. High expression of phosphorylated STAT1 (S727) was also confirmed in 44 pairs of human colon carcinoma and adjacent normal tissues. Taken together, the results showed that ruxolitinib decreased JAK1/2-STAT1-Mcl-1 protein level and effectively suppressed CRC cell proliferation in vitro and in vivo. Therefore, ruxolitinib could be a promising anticancer agent for CRC treatment. with those who did in the Pudong New Area of Shanghai of China (hazard ratio (HR)=1.46; 95% confidence interval (CI): 1.12-1.91) (3-5). Nevertheless, ~40% of patients who undergo surgery, which is applied in combination with chemotherapy or radiation therapy, subsequently experience local and systemic recurrence or resistance (6). Among primary risk factors, complex genomic alterations, which are essential in the mechanism of CRC pathophysiology, may induce resistance of CRC to drug therapy, thus making CRC the fourth most common cause of cancer-associated mortality (4,7). Consequently, investigating the mechanisms underpinning CRC chemosensitivity is important to improve treatment. Under pathological conditions, the Janus kinase (JAK)-STAT signaling pathway has been shown to regulate proliferation, differentiation and angiogenesis of malignant tumor cells and to promote the development of several malignant tumors, such as breast cancer and esophageal cancer (8,9). This pathway is constitutively activated in myeloproliferative diseases and in various solid tumors, including hepatocellular carcinomas, prostate, breast, head and neck, lung and CRC (10). Although the exact dysregulation mechanism of JAK/STAT signaling in CRC remains unclear, the JAK/STAT signaling pathway has been suggested as therapeutic target for the treatment of CRC (11,12). Myeloid cell leukemia-1 (Mcl-1) has sequence and functional similarity to Bcl-2 (13). Mcl-1 has a short half-life and is a highly regulated protein (14). The upstream regulatory kinase cascades of Mcl-1 transcription include JAK/STAT, PI3K and mitogen-activated protein kinases (15). Previous studies have suggested that Mcl-1 may have a significant part in th...

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Section: Discussionmentioning

confidence: 83%

Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2‑STAT1‑Mcl‑1 axis

Wang

Zhang

et al. 2021

Oncol Lett

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“…[1,21] In addition, a previous study revealed that aberrant expression of CLDN1 regulated AMPK/STAT1/ULK1 signaling pathway, lead to the promotion of proliferation and metastasis in esophageal squamous cancer. [29] Moreover, CLDN1 was experimentally demonstrated remarkably upregulated in CRC patients and could be considered as methylated diagnostic biomarker in CRC and normal control groups. [17] 2) EPHX4 (Epoxide Hydrolase 4) is a protein coding gene, which was signi cantly upregulated in rectal cancer con rmed by immunohistochemistry.…”

Section: Discussionmentioning

confidence: 99%

Identification of Methylation Driven Biomarkers for Diagnosis and Prognosis in Colon Cancer by Integrative Analysis of TCGA, GTEx, and GEO Data

Cao¹,

Chen²,

Yang³

2021

Preprint

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Background: The intention of the present work was to investigate methylation driven biomarkers for diagnosis and prognosis in colorectal cancer (CRC) by integrative analysis of DNA methylation and gene expression data from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO). Methods and Results: The differentially expression genes (DEGs) and differentially methylated genes (DMGs) were screened using mRNA expression and DNA methylation data from TCGA, respectively. And the methylation driven genes (MDGs) of CRC were further identified using MethylMix R package. Subsequently, the MDGs were underwent Random Forest (RF) analyses to establish diagnosis prediction model using mRNA expression data from TCGA and GTEx, which were then validated by GSE39582 from GEO dataset. In addition, prognostic biomarkers that were used to establish the methylation related risk score model was generated by the univariate and multivariate Cox regression analysis. 9 out of 10 DMGs revealed excellent performance as independent diagnostic predictors, including CLDN1, EPHX4, TCN1, ARHGAP20, LY6G6D, FAM150A, KCNJ12, KRT7 and STK33. Furthermore, STK33 and EPHX4 were found to be associated with Overall survival (OS). Conclusions: Our findings suggest that the identified MDGs could be potential biomarkers for diagnosis and prognosis of CRC.

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“…Furthermore, increased or decreased expression levels of CLDN1 have been found to be associated with several types of tumor; for example, overexpression of CLDN1 has been observed in nasopharyngeal, ovarian and oral squamous cell cancer (29). A number of studies have revealed that CLDN1 upregulation may contribute to tumor progression in esophageal squamous cell carcinoma, colon cancer and gastric carcinoma (30)(31)(32), while in other types of cancer, such as lung adenocarcinoma, CLDN1 acts as a tumor suppressor by activating the expression of matrix metallopeptidase-2 and high CLDN1 expression is associated with an improved prognosis (33). In prostate adenocarcinoma, Sheehan et al (34) demonstrated that patients with loss of CLDN1 protein expression had a higher rate of disease recurrence.…”

Section: Effect Of Claudin 1 On Cell Proliferation Migration and Apomentioning

confidence: 99%

Effect of claudin 1 on cell proliferation, migration and apoptosis in human cervical squamous cell carcinoma

et al. 2020

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Claudin 1 is a member of the claudin protein family that serves an important role in tight junctions. Increased or decreased expression levels of claudin 1 are found in several diseases, including breast cancer and viral infections. However, the function of claudin 1 in cervical cancer remains controversial. The aim of the present study was to investigate the biological functions of claudin 1 in different human cervical cancer cell lines. First, SiHa and ME-180 cells with stable claudin 1 overexpression or knockdown were established using lentiviral transduction, and the mRNA and protein levels were measured via reverse transcription-quantitative PCR and western blot analysis. Subsequently, cell proliferation, colony formation and migration experiments were performed in vitro using standard protocols, demonstrating that claudin 1 was able to inhibit cell proliferation and migration in both SiHa and ME-180 cells. Furthermore, cell cycle and apoptosis were detected via flow cytometry and western blotting, and the results revealed that claudin 1 inhibited cell cycle progression and promoted apoptosis. To further verify whether claudin 1 was involved in tumor growth in vivo , xenograft tumors were established in athymic mice via injecting SiHa cells overexpressing claudin 1, which was found to decrease tumor growth in vivo . Furthermore, the association between claudin 1 expression and prognosis was analyzed in different types of cancer in The Cancer Genome Atlas. Overall, the findings of the present study revealed that claudin 1 may serve an antitumor role in cervical squamous cell carcinoma and may be of value as a potential therapeutic target.

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CLDN1 induces autophagy to promote proliferation and metastasis of esophageal squamous carcinoma through AMPK/STAT1/ULK1 signaling

Cited by 37 publications

References 37 publications

Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2‑STAT1‑Mcl‑1 axis

Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2‑STAT1‑Mcl‑1 axis

Identification of Methylation Driven Biomarkers for Diagnosis and Prognosis in Colon Cancer by Integrative Analysis of TCGA, GTEx, and GEO Data

Effect of claudin 1 on cell proliferation, migration and apoptosis in human cervical squamous cell carcinoma

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