Abstract

c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members integrate signals that affect proliferation, differentiation, survival, and migration in a cell context- and cell type-specific way. JNK and p38 MAPK activities are found upregulated in nasopharyngeal carcinoma (NPC). Studies have shown that activation of JNK and p38 MAPK signaling can promote NPC oncogenesis by mechanisms within the cancer cells and interactions with the tumor microenvironment. They regulate multiple transcription activities and contribute to tumor-promoting processes, ranging from cell proliferation to apoptosis, inflammation, metastasis, and angiogenesis. Current literature suggests that JNK and p38 MAPK activation may exert pro-tumorigenic functions in NPC, though the underlying mechanisms are not well documented and have yet to be fully explored. Here, we aim to provide a narrative review of JNK and p38 MAPK pathways in human cancers with a primary focus on NPC. We also discuss the potential therapeutic agents that could be used to target JNK and p38 MAPK signaling in NPC, along with perspectives for future works. We aim to inspire future studies further delineating JNK and p38 MAPK signaling in NPC oncogenesis which might offer important insights for better strategies in diagnosis, prognosis, and treatment decision-making in NPC patients.

Highlights

  • Nasopharyngeal carcinoma (NPC) is one of the most aggressive types of head and neck carcinoma that mainly grows at the epithelial lining of the nasopharynx, with frequent metastasis to regional lymph nodes and occasionally to distal organs [1,2,3]

  • This review summarizes the potential therapeutics that could be used to target Jun N-terminal kinase (JNK) and p38 Mitogen-activated protein kinase (MAPK) signaling in NPC, along with perspectives for future works to address the research gaps

  • JNK1/2 was inactivated in human lung squamous cell carcinoma (LSCC) and their activities were positively correlated with survival rates of patients. p-JNK was overexpressed in papillary thyroid carcinomas and was significantly associated with the presence of lymph node metastases and advanced TNM stages

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Summary

Introduction

Nasopharyngeal carcinoma (NPC) is one of the most aggressive types of head and neck carcinoma that mainly grows at the epithelial lining of the nasopharynx, with frequent metastasis to regional lymph nodes and occasionally to distal organs [1,2,3]. Mitogen-activated protein kinase (MAPK) pathway is an intracellular signal transduction pathway that regulates a plethora of cellular processes, including cell growth, cell proliferation, cell differentiation, stress response, migration, and apoptosis, in response to various extracellular stimuli [12,13,14]. It consists of three pathways which involve extracellular-signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase 1, 2, and 3 (JNK1/2/3), and p38 MAPK signaling pathways (Figure 1) [15]. The activated MAPKs translocate to the nucleus and trigger cellular responses

JNK Signaling Pathway
JNK and p38 MAPK Signaling in Human Cancers
Pro-Tumorigenic Functions of JNK and p38 MAPK Signaling in NPC
Activation of JNK Signaling Promotes NPC Cell Survival
JNK and p38 MAPK Activities Inhibit Pro-Apoptotic Signaling in NPC Cells
JNK and p38 MAPK Signaling Mediates LMP1 in EBV-Associated NPC
Activation of p38 MAPK Signaling Promotes Inflammatory Tumor Microenvironment
Activation of p38 MAPK Signaling Promotes Angiogenesis
Tumor Suppressive Functions of JNK and p38 MAPK Signaling in NPC
Targeting JNK and p38 MAPK in NPC
Findings
Conclusions
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