CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway

Abstract

Chemokines and their receptors show a strong relationship with poor clinical outcomes in various cancers. However, their underlying mechanisms remain to be fully elucidated. In our research, we found C-C chemokine receptor 7 (CCR7) and its ligand chemokine ligand 21 (CCL21) were abnormally abundant in oral squamous cell carcinoma (OSCC) tissues, and CCR7 expression was correlated with poor prognosis of OSCC. After exogenous CCL21 stimulation, epithelial-mesenchymal transition (EMT) was promoted in OSCC cells, and cancer stem cell-related markers CD133, CD44, BMI1, ALDH1A1, and OCT4 increased. The migration, invasion, tumorsphere formation, and colony formation abilities of OSCC cells were enhanced, indicating that the stemness of OSCC cells was also improved. The knockdown and overexpression of CCR7 efficiently affected the CCL21-induced EMT and stemness of OSCC cells. When treated with CCL21, the phospho-JAK2 and phospho-STAT3 markedly increased. The inhibitor of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) significantly suppressed CCL21-induced EMT and stemness of OSCC cells. In conclusion, CCL21/CCR7 axis regulated EMT progress and promoted the stemness of OSCC by activating the JAK2/STAT3 signaling pathway. CCL21/CCR7 might be an effective target for OSCC prevention and treatment.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…Hypoxia [ 199 , 200 , 201 ] and prostaglandin E 2 (PGE 2 ) [ 202 , 203 ] increases the expression of CCR7 on a cancer cell ( Figure 4 ). CCR7 enhances proliferation [ 204 , 205 , 206 ] and stemness of cancer cells [ 207 , 208 , 209 ]. The activation of CCR7 increases angiogenesis by activating NF-κB and thus increases VEGF-A expression in esophageal squamous carcinoma cells [ 210 ].…”

“…These are growth factors responsible for lymphangiogenesis. The activation of CCR7 on a cancer cell causes EMT and migration of cancer cells [ 199 , 200 , 204 , 205 , 206 , 209 ]. In blood and lymphatic vessels CCR7 on cancer cells prevents anoikis [ 205 , 214 ].…”

The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review

“…Moreover, OCT4 induces the production of IL-24 through the STAT3 and NF-κB signaling pathways, which can confer radiotherapy resistance to breast cancer cells by inhibiting radiation-induced senescence (65). The recognition and combination of ligand chemokine ligand 21 (CCL21) and C-C chemokine receptor 7 (CCR7) increase the expression of pluripotency-related transcription factors and stem cell markers (such as OCT4, CD133, CD44) by activating the JAK2/STAT3 signaling pathway, thereby enhancing the invasion, migration, and tumorsphere formation of oral squamous cell carcinoma (100). In addition, the STAT3 or STAT5A plays an important role in glioblastoma, which can be verified by the expression of OCT4 (101).…”

Identification of Differential Methylation Regions and Correspondence Targeted Genes in Oral Squamous Cell Carcinoma

“…Recent study suggested that CCR7/CCL21 interaction can promote the lymph node of OSCC directly [22]. And CCR7/CCL21 interaction could also enhance the EMT process and promote stemness of OSCC by activating JAK2/STAT3 signal pathway [23]. Therefore, CCR7 is quite associated with the progression of OSCC.…”