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  • br Conflict statement br Introduction Prostate cancer PCa is

    2020-03-18


    Conflict statement
    Introduction Prostate cancer (PCa) is the second most frequently diagnosed cancer and the second leading cause of cancer death in men after lung cancer [1], [2]. The incidence and mortality rate of prostate cancer are significantly higher in developed countries especially the United States, where 186,000 new cases are diagnosed and 28,600 deaths occurred due to it in 2008 [3]. In the United Kingdom, the statistic data was about 35,000 cases and 10,000 deaths annually [4]. The skeleton is the most frequent metastatic site for aggressive prostate cancer, with a frequency of nearly 80%. Prostate cancer bone metastases cause intractable pain, spinal cord compression, pathologic fracture, hypercalcemia, and lead to poor quality of life as well as reduced life expectancy [5]. The progression of prostate cancer metastasizing to the bones is a complex process involving bone-tumor cell crosstalk mediated by various cytokines and factors [6], [7]. In the bone metastatic site, PCa dexamethasone acetate secrete factors to stimulate matrix resorption and bone destruction, and cytokines (such as TGF-β) are released to facilitate PCa cells with active proliferation and dissemination capacities [8], [9]. On the other hand, PCa cells produce multiple osteolytic mediators to cause further bone resorption and the so-called vicious cycle [10], among which parathyroid hormone-related protein (PTHrP) is probably the most important one, since approximately 90% of prostate cancer patients with bone metastases have elevated levels of PTHrP. Tumor cell derived PTHrP binds to its receptor PTHR1 on osteoblast and stimulates the osteoblast express receptor activator of nuclear factor κB ligand (RANKL), which is responsible for the induction of osteoclast differentiation and activation [11], [12], [13], [14], [15]. Bone metastatic prostate cancer cells highly express bone-related genes that contribute to osteomimetic characteristics [16]. Runt-related transcription factor 2 (Runx2, also known as Osf2/Cbfa1, AML3, or Pebp2αA), a crucial transcription factor in osteogenic commitment, is one of the most significant osteomimetic genes [17], [18]. Runx2 plays important roles in prostate cancer bone metastasis via regulating the expression of RANKL, osteopontin (OPN), bone sialoprotein (BSP), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 2, 9, 13 (MMP2, 9, 13) to participate in bone turnover [19], [20]. Runx2 responds to TGF-β stimulation by up-regulating the expression of Indian hedgehog (IHH), which in turn increases the level of PTHrP [21]. Blockade of the Runx2-IHH axis in breast cancer cells by targeting Runx2 with short hairpin RNA prevents osteolytic disease [22]. Discoidin dexamethasone acetate domain receptor 2 (DDR2) belongs to the receptor tyrosine kinase (RTK) family and is activated by collagen binding [23], [24]. A unique feature that distinguishes DDR2 from other RTKs is that its activation by collagen is very slow and sustained (by hours), compared to the rapid response of typical RTKs to their ligands (by seconds to minutes) [24]. The main functions of DDR2 are to 1) control the remodeling of ECM by regulating the expression and activity of MMPs [25], [26], [27], 2) promote cell proliferation, adhesion and migration [28], [29], [30], [31], [32], 3) stimulate osteoblast differentiation and bone formation by regulation of the transcription activity and phosphorylation of Runx2 in an ERK MAPK-dependent manner [33], [34]. In tumor, DDR2 participates in the process of melanoma liver metastasis [35], colorectal cancer metastasis [36], as well as the progression of nasopharyngeal carcinoma (NPC) [37], aneuploid papillary thyroid carcinomas [38], and breast carcinoma [39], [40], [41]. Furthermore, DDR2 is up-regulated by TGF-β and is involved in TGF-β-induced EMT in A549 lung cancer cells [42]. In the present study, we demonstrate that DDR2 is highly expressed in bone metastatic PCa cells and tissues, and is associated with increased motility and invasiveness of PCa cells. DDR2 promoted activation of osteoblast and osteoclast in vitro and boosted the formation of osteolytic lesions in vivo. We also elucidated the underlying mechanism that DDR2 regulates PTHrP via modulating the phosphorylation and transactivity of Runx2. In addition, DDR2 was involved in TGF-β-mediated bone resorption, and facilitated the adhesion of PCa cells to type I collagen. Our study aims to provide a novel potential target for PCa treatment in future.