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

Abstract

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.

The m7G Reader NCBP2 Promotes Pancreatic Cancer Progression by Upregulating MAPK/ERK Signaling

“…To verify our assumption, we reviewed relevant literature and found that c-JUN could directly activate the MEK/ERK signaling pathway. Knockdown of c-JUN dramatically inhibits the phosphorylation level of MEK and ERK [37,38]. In line with these, knockdown of c-JUN significantly inhibited the activation of MEK/ERK signaling in PDAC cells (Figure 5D).…”

Downregulated CDK10 promotes cancer progression and radioresistance in lung cancer through activating the JNK/c-Jun signaling pathway

“…CDK10 inhibited lung cancer cell growth and metastasis by inhibition of the ETS2/c-Raf/p-MEK/p-ERK signaling loop ( 8 ). The evidence was well established that the JNK/c-Jun signaling pathway was associated with cell proliferation, migration, invasion, and radioresistance in various cancers ( 20 , 21 , 29 , 30 ). In our study, we identified the JNK/c-Jun signaling as a new downstream pathway regulated by CDK10 in lung cancer cells by RNA sequencing analysis.…”

“…The activation of JNK/c-Jun signaling was reported to facilitate tumor progression and metastasis in lung adenocarcinoma and extrahepatic cholangiocarcinoma ( 18 , 19 ). Moreover, c-Jun augmented the radioresistance in nasopharyngeal carcinoma and liver cancer ( 20 , 21 ). Therefore, JNK/c-Jun signaling is closely related to cancer progression and radioresistance.…”