CCR9 Promotes Migration and Invasion of Lung Adenocarcinoma Cancer Stem Cells.

Aim: CC chemokine receptor 9 (CCR9) interacts with its exclusive ligand CCL25, resulting in promoting tumor progression and metastasis. However, the effect and mechanisms of CCR9 on lung adenocarcinoma distant metastasis remain largely unknown. To preliminary clarify the underlying mechanisms, we investigate the correlation between CCR9 and ALDH1A1+cancer stem cells (CSCs), as well as the effect of CCR9 on the migration and invasion of CSCs. Methods: Immunohistochemistry was performed to detect the expression of CCR9 in lung adenocarcinoma tissues. The correlations of CCR9 with distant metastasis and overall survival were investigated. Serial paraffin-embedded tissue blocks were used to detect ALDH1A1+CSCs expression. The correlations between CCR9 expression and ALDH1A1+CSCs were evaluated. We further studied the effect of CCR9/CCL25 on the migration and invasion of CSCs using transwell assays. Results: There were positive correlations between CCR9 expression and distant metastasis, as well as poor overall survival. Patients with high CCR9 expression were more likely to develop distant metastasis and demonstrated poorer overall survival than patients with low CCR9 expression. In addition, there was positive correlation between the expression of CCR9 and ALDH1A1 in the same tumor microenvironment. ALDHhigh CSCs demonstrated enhanced expression of CCR9 than ALDHlow cells. Further transwell assays demonstrated that the numbers of CSCs migrated or invaded in response to CCL25 were more than that without CCL25 stimulation. Additional application of anti-CCR9 antibody reversed the CCL25-induced migration and invasion of CSCs. Conclusions: In summary, our study demonstrated that CCR9/CCL25 promoted the migration and invasion of CSCs, which might contribute to distant metastasis and poor overall survival. Our findings provided evidence that CCR9/CCL25 could be used as novel therapeutic targets for lung adenocarcinoma.

Lu L ，Du H ，Huang H ，Wang C ，Wang P ，Zha Z ，Wu Y ，Liu X ，Weng C ，Fang X ，Li B ，Mao H ，Wang L ，Guan M ，Liu G ... -  《International Journal of Medical Sciences》

CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion.

Johnson EL ，Singh R ，Singh S ，Johnson-Holiday CM ，Grizzle WE ，Partridge EE ，Lillard JW Jr ... -  《World Journal of Surgical Oncology》

Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer.

Singh R ，Stockard CR ，Grizzle WE ，Lillard JW Jr ，Singh S ... -  《-》

Expression of CC chemokine receptor 9 predicts poor prognosis in patients with lung adenocarcinoma.

Zhong Y ，Jiang L ，Lin H ，Li B ，Lan J ，Liang S ，Shen B ，Lei Z ，Zheng W ... -  《Diagnostic Pathology》

CCL25/CCR9 interaction promotes the malignant behavior of salivary adenoid cystic carcinoma via the PI3K/AKT signaling pathway.

CC chemokine receptor 9 (CCR9), an organ-specific chemokine receptor, interacts with its exclusive ligand CCL25 to promote tumor proliferation and metastasis. However, the effect of CCR9 on salivary adenoid cystic carcinoma (SACC) malignant behavior remains unknown. This study aimed to investigate the specific molecular mechanism by which CCR9/CCL25 modulates malignant progression in SACC. Immunohistochemistry staining and RT-qPCR analyses were performed to detect the correlation of CCR9 expression and tumor progression-associated markers in SACC. In vitro, SACC cell proliferation and apoptosis were evaluated using Cell Counting Kit-8 and colon formation, and cell migration and invasion were detected by wound healing and transwell assays. Vercirnon was used as an inhibitor of CCR9, and LY294002 was used as an inhibitor of the PI3K/AKT pathway in this study. Western blot and RT-qPCR assays were carried out to measure the downstream factors of the interaction of CCL25 and CCR9. The effect of CCL25 on the development of SACC in vivo was examined by a xenograft tumor model in nude mice following CCL25, Vercirnon and LY294002 treatment. CCR9 was highly expressed in SACC compared with adjacent salivary gland tissues, and its level was associated with tumor proliferation and metastases. CCL25 enhanced cell proliferation, migration, and invasion through its interaction with CCR9 and exerted an antiapoptotic effect on SACC cells. Targeting CCR9 via Vercirnon significantly reduced the phosphorylation level of AKT induced by CCL25. CCL25/CCR9 could activate its downstream factors through the PI3K/AKT signaling pathway, such as cyclin D1, BCL2 and SLUG, thus promoting SACC cell proliferation, antiapoptosis, invasion and metastasis. The in vivo data from the xenograft mouse models further proved that CCL25 administration promoted malignant tumor progression by activating the PI3K/AKT pathway. The interaction of CCL25 and CCR9 promotes tumor growth and metastasis in SACC by activating the PI3K/AKT signaling pathway, offering a promising strategy for SACC treatment.

Chai S ，Wen Z ，Zhang R ，Bai Y ，Liu J ，Li J ，Kongling W ，Chen W ，Wang F ，Gao L ... -  《PeerJ》