Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL-17/IL-17R-JAK2/STAT3 signaling pathway

Abstract

Abstract. The interleukin (IL)-17/IL-17 receptor (IL-17R)complex has been shown to be important for the regulation of inflammation; however, its role in the regulation of tumor processes has recently emerged as a research focus. The present study demonstrated that oxaliplatin was able to increase the levels of IL-17/IL-17R in hepatocellular carcinoma (HCC) patients and cells lines, and that it had important roles in reducing the susceptibility of the cells to oxaliplatin-induced apoptosis. Furthermore, the expression of autophagy-related proteins was induced by IL-17/IL-17R and autophagy was shown to induce resistance to oxaliplatin in HCC. In addition, the janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was shown to be an important pathway in the induction of autophagy in response to oxaliplatin. Autopjhagy was inhibited by 3-methyladenine and JAK2/STAT3 signaling was blocked by AG490, which induced apoptosis in SMMC7721 cells treated with oxaliplatin. The results of the present study may help to elucidate the mechanism underlying the role of IL-17/IL-17R-induced autophagy in the chemoresistance of HCC, as well as help to establish and develop measures to overcome chemoresistance in HCC. IntroductionHepatocellular carcinoma (HCC) is a major malignancy worldwide and its incidence is increasing annually; it is the second most common cause of cancer-associated mortality (1).The majority of patients have a low survival rate as a result of locally advanced or metastatic diseases, and surgery is feasible for only a small percentage of patients with HCC. Therefore, chemotherapy is the optimal therapeutic strategy for inoperable HCC (2). Oxaliplatin has been widely used in chemotherapy to reduce tumor recurrence and prolong survival in patients with HCC because of its fewer side effects compared with other platinum drugs (3). However, chemoresistance to oxaliplatin in the form of suppressed HCC apoptosis is commonly observed (4).Interleukin-17 (IL-17) is predominantly secreted by interleukin-17-producing T-helper (Th17) cells, which participate in the progression and pathogenesis of inflammatory diseases (3). The IL-17 receptor (IL-17R) is expressed on the surface of numerous cells, including macrophages, dendritic cells, epithelial cells, fibroblasts and T lymphocytes (5,6). Previous studies reported that IL-17-producing cells accumulated in tumors (7,8), and that patients with malignant serum effusions (9) or multiple myeloma (10) showed significantly higher serum levels of IL-17. Furthermore, patients with persistently higher levels of IL-17 demonstrated the requirement for longer courses of chemotherapy, since these patients comprised a significant proportion of all cases of recurrence (11). Typically, IL-17 does not engage with Toll/IL-1 receptor (TIR) domain-containing adaptors, such as MyD88, TIR domain-containing adapter protein inducing interferon-β or IL-1 receptor-associated kinases (12). Rather, IL-17 signals through nuclear factor (NF)-κB (13), mitogen-activated pro...

Cajanonic acid A regulates the ratio of Th17/Treg via inhibition of expression of IL-6 and TGF-β in insulin-resistant HepG2 cells

“…Along with accumulation of T cells, there is an imbalance between the pro-inflammatory T-cell subset known as T helper 17 (Th17) and the T helper 1 and anti-inflammatory T-cell subset known as regulatory T cells (Tregs). Th17 cells secrete a series of cytokines including IL-17A (IL-17), IL-17F, IL-22, IL-6, and TNF-a [9,10]. The shift in the ratio of Th17/Treg from T cells is mediated by IL-6 and TGF-β [11,12].…”

Long Noncoding RNA HOST2 Promotes Epithelial-Mesenchymal Transition, Proliferation, Invasion and Migration of Hepatocellular Carcinoma Cells by Activating the JAK2-STAT3 Signaling Pathway

“…As an LncRNA, HOST2 expression is strongly associated with cancer development and progression [39]. The JAK2/STAT3 signaling pathway was shown to be a crucial pathway in the induction of autophagy in response to oxaliplatin [40]. Despite that tyrosine kinase signaling occurs through multiple pathways, signal transducer and activation of transcription 3 (STAT3) is a point of convergence for many nonreceptor and receptor tyrosine kinases and is constitutively activated and expressed at a high frequency in a wide range of cancer cells [41].…”

IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway

“…Following engagement of the IL-17RA/C receptor complex in neurons by IL-17A, nonreceptor tyrosine kinases could be recruited to the SEFIR domain in the receptor complex, resulting in the consecutive recruitment of downstream signaling pathways. IL-17A could induce autophagy via Janus kinase/signal transducer (JAK2/STAT3) and c-Jun N-terminal kinase (JNK) signaling pathway in human SMMC-7721 cells and osteoclast precursors (OCPs), respectively (11,12). On the contrary, IL-17A inhibited autophagy via TAB2/TAB3-p38 mitogen-activated protein kinase pathways and mTOR signaling in Hepatocellular carcinoma (HCC) cells and keratinocytes (13,14).…”