CCL21/CCR7 interaction promotes cellular migration and invasion via modulation of the MEK/ERK1/2 signaling pathway and correlates with lymphatic metastatic spread and poor prognosis in urinary bladder cancer

Abstract

Lymph node metastasis in patients with urinary bladder cancer (UBC) is always associated with poor prognosis and is the determinant for tumor staging and the development of treatment regimens; however, its underlying mechanisms remain to be studied. Immunohistochemical staining of tumor sections from 62 UBC patients was performed using CCR7, D2-40 and CD34 antibodies. We showed that increased CCR7 expression was significantly associated with positive lymph node status (P=0.008), pT3-T4 tumor stage (P=0.015), tumor grade (P=0.010) and worse overall survival (OS, P<0.001) and that both CCR7 expression and lymph node metastasis were independent prognostic factors for OS (P=0.031 and P=0.001, respectively) based on multivariate analysis. We found that there was a significant association between MLVD and lymph node status (P=0.006), but this relation was not observed for MVD. Furthermore, we showed that increased CCR7 expression correlated significantly with higher MLVD (P=0.014) and MVD (P=0.002). Wound-healing and Matrigel Transwell assays indicated that activation of CCR7 with CCL21 significantly enhanced the invasion and migration abilities of UM-UC-3 cells, and this enhanced effect was significantly abrogated by CCR7 knockdown using siRNA. Western blot analysis revealed that the phospho-ERK1/2 level was markedly increased when UM-UC-3 cells were treated with CCL21 and significantly decreased when the CCR7 gene was silenced. MEK/ERK1/2 inhibition with PD98059 significantly suppressed the migration and invasion abilities of UM-UC-3 cells and also significantly abrogated the effects of CCL21/CCR7 on cell migration and invasion. Based on these results, we conclude that activation of the CCL21/CCR7 chemoaxis promotes lymph node metastasis of UBC in at least two ways. Firstly, although CCR7 is a promoting factor that induces both lymphangiogenesis and angiogenesis, it may promote lymph node metastasis through its lymphangiogenic effect rather than through its angiogenic effect. Secondly, the CCL21/CCR7 chemoaxis promotes the migration and invasion of UBC cells via the MEK/ERK1/2 signaling pathway rather than the PI3K/AKT pathway.

Chemokine CCL4 Induces Vascular Endothelial Growth Factor C Expression and Lymphangiogenesis by miR-195-3p in Oral Squamous Cell Carcinoma

“…Moreover, CCL21/CCR7 signalings VEGF-C expression and secretion and promotes breast cancer-induced lymphangiogenesis via LEC activation ( 42 ). Clinicopathological data also show that chemokines and their receptors are involved in tumor lymphatic metastasis; for example, CCL21/CCR7 expression is related to poor outcomes in urinary bladder cancer ( 43 ). In this study, CM from CCL4-treated OSCC cells promoted tube formation and migration in LECs, indicating that CCL4 enhances lymphangiogenesis in OSCC cells.…”

Identification of Novel Long Non-coding and Circular RNAs in Human Papillomavirus-Mediated Cervical Cancer

“…et al, 2017 ), and it also exhibits transcriptional repression by epigenetic inactivation in specific cervical cancer cell lines, thus it may contribute to the constitutive activation of the Wnt signaling pathway in cervical carcinogenesis ( Lee et al, 2008 ). A large number of studies have demonstrated that chemokines are involved in the progression, migration, and survival of cancers, such as CXCL12 (ENSG00000107562), CCL21 (ENSG00000137077), and especially CCL19 (ENSG00000172724), which is associated with progression of cervical cancer ( Teicher and Fricker, 2010 ; Xiong et al, 2017 ; Zhang et al, 2017 ). Homeobox B13 (HOXB13, ENSG00000159184) is a susceptibility gene for prostate cancer ( Xu et al, 2013 ).…”

The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression

“…It also plays a critical role in the progression of many different malignancies such as breast [31], gastric [32], skin (melanoma) [33], head and neck [34], lung [35], esophageal [36], hepatocellular [37], cervical [38], thyroid [39], tonsillar [40], colorectal [41] and prostate cancers [42] as summarized in (Table 1). In the majority of these cancers, larger tumor size and deeper invasion was associated with CCR7 expression [43]. Taken together, the CCR7-mediated cell migration underlies a broad range of immune system activities and therefore it is important to understand its mechanism.…”

“…[18,[44][45][46] Human Bladder Cancer Enhances the migration, invasion and tumor proliferation/ correlates with poor prognosis. [43,47] Cervical Cancer Metastasis and poor prognosis. [38,40] Colorectal Cancer Poor prognosis and metastasis.…”