CCR7 regulates ANO6 to promote migration of pancreatic ductal adenocarcinoma cells via the ERK signaling pathway

Abstract

The increase in migratory ability of pancreatic ductal adenocarcinoma cells is a key event in the development of metastasis to the lymph nodes and distant organs. Although the C-C motif chemokine receptor 7 (CCR7) and its ligand, C-C motif chemokine ligand 21 (CCL21), have been revealed to serve an important role in tumor migration, their precise roles and potential underlying mechanisms remain largely unknown. The present study revealed that overexpression of CCR7 significantly promoted BxPC-3 cell migration, accompanied by the induction of anoctamin 6 (ANO6) expression, indicating that ANO6 is a downstream target of CCR7 signaling. Furthermore, the level of phosphorylated extracellular signal-regulated kinase (ERK) was significantly increased in CCR7-overexpressing BxPC-3 cells, indicating that ERK may be a potential mediator of CCR7-regulated ANO6 expression in BxPC-3 cells. To characterize the receptor-mediated pathway, a specific ERK inhibitor, U0126, was used, which reduced BxPC-3 cell migration and the expression of ANO6. In summary, the results of the present study demonstrate that CCR7 promoted BxPC-3 cell migration by regulating ANO6 expression perhaps via activation of the ERK signaling pathway.

Molecular underpinning of intracellular pH regulation on TMEM16F

“…Given that intracellular alkalization is one of the hallmarks of cancer cells (Cardone, Casavola and Reshkin, 2005; White, Grillo-Hill and Barber, 2017) and TMEM16F is highly expressed in a wide spectrum of tumors (Jacobsen et al ., 2013; Wang et al ., 2018; Xuan, Wang and Xie, 2019), we next sought to examine whether endogenous TMEM16F in tumor cells can also be strongly promoted by intracellular alkalization as we observed in the HEK293 cells exogenously expressed with TMEM16F. To address this, we utilized a human choriocarcinoma cell line BeWo that highly expresses TMEM16F CaPLSases to enable cell-cell fusion of the placental trophoblast tumor cells (Zhang et al ., 2020).…”

“…TMEM16F has been identified in a wide variety of cancer cells; and according to the Human Protein Atlas (http://www.proteinatlas.org), the high expression level of TMEM16F is associated with the overall prognosis of a number cancers including breast and cervical cancers. Although it is unclear how TMEM16F contributes to tumor growth and cancer progression, it has been reported that genetic manipulations of TMEM16F can change cancer cell proliferation and migration (Jacobsen et al ., 2013; Wang et al ., 2018; Xuan, Wang and Xie, 2019). Interestingly, loss of membrane phospholipid asymmetry is a salient feature of many cancerous cells, whose cell surfaces display an elevated amount of PS (Riedl et al ., 2011; Zhao et al ., 2011).…”

“…Nevertheless, it is not known if TMEM16F’s phospholipid scrambling and ion channel activities can also be regulated by pH i . Interestingly, TMEM16F is highly expressed in various tumor cells including the pancreatic ductal adenocarcinoma cells (Wang et al ., 2018), glioma cells (Xuan, Wang and Xie, 2019), and choriocarcinoma BeWo cells (Zhang et al ., 2020). Consistent with its high expression level, TMEM16F has been implicated in tumor cell proliferation, migration and metastasis (Jacobsen et al ., 2013; Wang et al ., 2018; Xuan, Wang and Xie, 2019).…”

“…Interestingly, TMEM16F is highly expressed in various tumor cells including the pancreatic ductal adenocarcinoma cells (Wang et al ., 2018), glioma cells (Xuan, Wang and Xie, 2019), and choriocarcinoma BeWo cells (Zhang et al ., 2020). Consistent with its high expression level, TMEM16F has been implicated in tumor cell proliferation, migration and metastasis (Jacobsen et al ., 2013; Wang et al ., 2018; Xuan, Wang and Xie, 2019). Given the fact that pH dysregulation (intracellular alkalization to pH i 7.3-7.6 and extracellular acidification to pH 6.8-7.0) is one of the hallmarks of cancer (Webb et al ., 2011; White, Grillo-Hill and Barber, 2017), it is thus critical to understand whether pH i can regulate TMEM16F ion channel and CaPLSase activities.…”

Identification and Interaction Analysis of Molecular Markers in Pancreatic Ductal Adenocarcinoma by Integrated Bioinformatics Analysis and Molecular Docking Experiments

“…Then, GO and REACTOME pathway analyses were used to investigate the interactions of these DEGs. Increasing evidence shows that LAPTM4B [52], CEACAM6 [53], SERPINE2 [54] and VNN1 [55], SPHK1 [56], HRG (histidine rich glycoprotein) [57], VEGFC (vascular endothelial growth factor C) [58], ANXA3 [59], APOA2 [60], LCN2 [61], TIMP1 [62], CD63 [63], CD151 [64], MAL2 [65], ARNTL2 [66], PKD2 [67], E2F1 [68], MMP1 [69], CCR7 [70], NOTCH2 [71], BTLA (B and T lymphocyte associated) [72], TFRC (transferrin receptor) [73], CD4 [74], ATM (ATM serine/threonine kinase) [75], LEF1 [76], CSF1R [77], CTSB (cathepsin B) [78], DUSP2 [79] and NR4A1 [80] are closely associated with progression of PDAC. PTGER3 [81] and MAGI2 [82] are linked with angiogenesis, chemoresistance, cell proliferation and migration in ovary cancer, but these genes might be liable for growth PDAC.…”