High Expression of IL-4R Enhances Proliferation and Invasion of Hepatocellular Carcinoma Cells

Guo, Changkuo; Ouyang, Yuming; Cai, Jing; Xiong, Le; Chen, Yajie; Zeng, Xiaoli; Liu, Anwen

doi:10.5301/ijbm.5000280

Cited by 11 publications

(9 citation statements)

References 28 publications

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“…They designed the IL4-Pseudomonas exotoxin (IL4-PE) conjugate and the treatment of IL4-PE decreased the colony formation ability of thyroid cancer cells and tumor growth in thyroid xenograft tumor model [64]. Furthermore, IL4R plays an essential role in regulating hepatocellular carcinoma (HCC) cell survival, proliferation, and metastasis and regulates the activation of JAK1/STAT6 and Jnk/Erk1/2 pathways [65]. As shown in the Figure 2G, interestingly, the knockdown of the IL4R complex component caused the downregulation of each other.…”

Section: Discussionmentioning

confidence: 99%

Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways

Kang

Lee

et al. 2019

Cancers

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Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that a significant association between mRNA level of IL4Rα or IL13Rα1 and the poor prognosis of renal cell carcinoma (RCC) from the public database (http://www.oncolnc.org/). Then, we evaluated the clinicopathological significance of the immunohistochemical expression of IL4Rα and IL13Rα1 in 199 clear cell RCC (CCRCC) patients. The individual and co-expression patterns of IL4Rα and IL13Rα1 were significantly associated with cancer-specific survival (CSS) and relapse-free survival (RFS) in univariate analysis. Multivariate analysis indicated IL4Rα-positivity and co-expression of IL4Rα and IL13Rα1 as the independent indicators of shorter CSS and RFS of CCRCC patients. For the in vitro evaluation of the oncogenic role of IL4Rα and IL13Rα1 in RCC, we knock-downed IL4Rα or IL13Rα1 and observed that the cell proliferation rate was decreased, and the apoptosis rate was increased in A498 and ACHN cells. Furthermore, we examined the possible role of Janus kinase 2 (JAK2), well-known down-stream tyrosine kinase under the heterodimeric receptor complex of IL4Rα and IL13Rα1. Interestingly, JAK2 interacted with Forkhead box O3 (FOXO3) to cause tyrosine-phosphorylation of FOXO3. Silencing IL4Rα or JAK2 in A498 and ACHN cells reduced the interaction between JAK2 and FOXO3. Moreover, pharmacological inhibition of JAK2 induced the nuclear localization of FOXO3, leading to increase apoptosis and decrease cell proliferation rate in A498 and ACHN cells. Taken together, these results suggest that IL4Rα and IL13Rα1 might be involved in the progression of RCC through JAK2/FOXO3 pathway, and their expression might be used as the novel prognostic factor and therapeutic target for RCC patients.

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Section: Discussionmentioning

confidence: 99%

Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways

Kang

Lee

et al. 2019

Cancers

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“…Moreover, it has been demonstrated that downregulation of IL-4/IL-13 receptors showed suppression of tumor activity in other cancers. Guo et al showed that downregulation of IL-4R led to enhanced apoptosis, diminished proliferation, and reduced invasion of hepatocellular carcinoma cells, and abolished IL-4-induced activation of JAK/STAT6 and JNK/ERK1/2 signaling pathways [ 129 ]. Venmar and colleagues reported that IL-4Rα-downregulation decreased metastatic capacity in breast cancer [ 62 ].…”

Section: Future Directions Of Researchmentioning

confidence: 99%

Involvement of IL-4, IL-13 and Their Receptors in Pancreatic Cancer

Shi

Song

Traub

et al. 2021

IJMS

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Interleukin (IL)-4 and IL-13 are known as pleiotropic Th2 cytokines with a wide range of biological properties and functions especially in immune responses. In addition, increasing activities have also been determined in oncogenesis and tumor progression of several malignancies. It is now generally accepted that IL-4 and IL-13 can exert effects on epithelial tumor cells through corresponding receptors. Type II IL-4 receptor (IL-4Rα/IL-13Rα1), predominantly expressed in non-hematopoietic cells, is identified to be the main target for both IL-4 and IL-13 in tumors. Moreover, IL-13 can also signal by binding to the IL-13Rα2 receptor. Structural similarity due to the use of the same receptor complex generated in response to IL-4/IL-13 results in overlapping but also distinct signaling pathways and functions. The aim of this review was to summarize knowledge about IL-4 and IL-13 and their receptors in pancreatic cancer in order understand the implication of IL-4 and IL-13 and their receptors for pancreatic tumorigenesis and progression and for developing possible new diagnostic and therapeutic targets.

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“…Elevated plasma level of IL-4 was revealed in liver cancer (Talaat et al, 2016). Interestingly, it has been reported that IL-4 induces the activation of the JNK/extracellular signal-regulated kinase (ERK)1/2 pathway to promote the tumorigenesis of HCC (C. Guo et al, 2017).…”

Section: Cell Ell B Biology Iology I International Nternationalmentioning

confidence: 99%

“…Elevated plasma level of IL‐4 was revealed in liver cancer (Talaat et al, 2016). Interestingly, it has been reported that IL‐4 induces the activation of the JNK/extracellular signal‐regulated kinase (ERK)1/2 pathway to promote the tumorigenesis of HCC (C. Guo et al, 2017). Notably, the ERK pathway displayed hyper‐activation in HCC, mediated the cell growth, and shared correlation with the drug resistance (Nwosu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

c‐Jun‐mediated JMJD6 restoration enhances resistance of liver cancer to radiotherapy through the IL‐4‐activated ERK pathway

Liu

Sui

Sun

et al. 2023

Cell Biology International

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Radiotherapy is widely used in the treatment of liver cancer, but the efficacy can be limited by radioresistance. In this study, we attempt to delineate the possible molecular mechanism of c-Jun-regulated Jumonji domain-containing protein 6/interleukin 4/extracellular signal-regulated kinase (JMJD6/IL-4/ERK) axis in radioresistance of liver cancer. The expression of c-Jun was quantified in liver cancer tissues and cell lines, and the results indicated that c-Jun was upregulated in liver cancer tissues and cells. We further illustrated the role of c-Jun following gain-and loss-of-function strategies in malignant phenotypes of liver cancer cells. It was established that c-Jun elevated JMJD6 expression and augmented the malignancy and aggressiveness of liver cancer cells. The in vivo effects of c-Jun on radioresistance in liver cancer were validated in nude mice, in response to IL-4 knockdown or the ERK pathway inhibitor, PD98059. In the presence of JMJD6 upregulation, the expression of IL-4 was elevated in mice with liver cancer, which enhanced the radiation resistance. Moreover, knockdown of IL-4 inactivated the ERK pathway, thereby reversing the radiation resistance caused by overexpressed JMJD6 in tumor-bearing mice. Taken together, c-Jun augments the radiation resistance in liver cancer by activating the ERK pathway through JMJD6-upregulated IL-4 transcription.

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High Expression of IL-4R Enhances Proliferation and Invasion of Hepatocellular Carcinoma Cells

Abstract: IL-4R plays an important role in regulating HCC cell survival and metastasis, and regulates the activity of the JAK1/STAT6 and JNK/ERK1/2 signaling pathways. We therefore suggest that IL-4/IL-4R may be a new therapeutic target for HCC.

Cited by 11 publications

References 28 publications

Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways

Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways

Involvement of IL-4, IL-13 and Their Receptors in Pancreatic Cancer

c‐Jun‐mediated JMJD6 restoration enhances resistance of liver cancer to radiotherapy through the IL‐4‐activated ERK pathway

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