Abstract
The tumor necrosis factor (TNF) receptor superfamily member 11a (TNFRSF11a, also known as RANK) was demonstrated to play an important role in tumor metastasis. However, the specific function of RANK in colorectal cancer (CRC) metastasis and the underlying mechanism are unknown. In this study, we found that RANK expression was markedly upregulated in CRC tissues compared with that in matched noncancerous tissues. Increased RANK expression correlated positively with metastasis, higher TNM stage, and worse prognosis in patients with CRC. Overexpression of RANK promoted CRC cell metastasis in vitro and in vivo, while knockdown of RANK decreased cell migration and invasion. Mechanistically, RANK overexpression significantly upregulated the expression of tartrate-resistant acid phosphatase 5 (TRAP/ACP5) in CRC cells. Silencing of ACP5 in RANK-overexpressing CRC cells attenuated RANK-induced migration and invasion, whereas overexpression of ACP5 increased the migration and invasion of RANK-silencing cells. The ACP5 expression was transcriptionally regulated by calcineurin/nuclear factor of activated T cells c1 (NFATC1) axis. The inhibition of calcineurin/NFATC1 significantly decreased ACP5 expression, and attenuated RANK-induced cell migration and invasion. Furthermore, RANK induced phospholipase C-gamma (PLCγ)-mediated inositol-1,4,5-trisphosphate receptor (IP3R) axis and stromal interaction molecule 1 (STIM1) to evoke calcium (Ca2+) oscillation. The RANK-mediated intracellular Ca2+ mobilization stimulated calcineurin to dephosphorylate NFATC1 and induce NFATC1 nuclear translocation. Both blockage of PLCγ-IP3R axis and STIM1 rescued RANK-induced NFATC1 nuclear translocation, ACP5 expression, and cell metastasis. Our study revealed the functional expression of RANK in human CRC cells and demonstrated that RANK induced the Ca2+-calcineurin/NFATC1-ACP5 axis in the regulation of CRC metastasis, that might be amenable to therapeutic targeting.
Highlights
The tumor necrosis factor (TNF) receptor superfamily member 11a (TNFRSF11a, known as RANK) and its ligand TNF superfamily member 11 were first identified as pivotal regulators of osteoclast development in the late 1990s.Membrane-bound or soluble RANKL from osteoblasts interacts with RANK-expressing pre-osteoclasts to induce osteoclast differentiation for bone remodeling[2]
We investigated whether RANK expressed on colorectal cancer (CRC) cells displayed similar downstream signaling to osteoclasts and secreted osteoclast-specific genes to degrade surrounding tissue for metastasis
Approximately 25% of patients with CRC present with metastases at initial diagnosis and almost 50% develop metastases, leading to the high mortality rates observed in CRC34
Summary
The tumor necrosis factor (TNF) receptor superfamily member 11a (TNFRSF11a, known as RANK) and its ligand TNF superfamily member 11 ( known as RANKL) were first identified as pivotal regulators of osteoclast development in the late 1990s Membrane-bound or soluble RANKL from osteoblasts interacts with RANK-expressing pre-osteoclasts to induce osteoclast differentiation for bone remodeling[2]. Over the past two decades the RANKL/RANK axis has been identified as a critical signaling pathway involved in several mechanisms beyond bone homeostasis, most notably in cancer cell migration and bone development[3]. Abundant RANKL in the bone environment was identified early as a chemoattractant for bone-specific metastasis of epithelial tumors and melanoma that expressed RANK4. Official journal of the Cell Death Differentiation Association
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