ZIP4 silencing improves bone loss in pancreatic cancer

Zhang, Qiang; Sun, Xiaotian; Yang, Jingxuan; Ding, Hao; LeBrun, Drake G.; Ding, Kai; Houchen, Courtney W.; Postier, Russell G.; Ambrose, Catherine G.; Li, Zhao‐Shen; Bi, Xiaohong; Li, Min

doi:10.18632/oncotarget.4667

Cited by 18 publications

(11 citation statements)

References 47 publications

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“…Indeed, it was recently reported that animals bearing the Lewis Lung carcinoma present muscle wasting associated with decreased BMD, although alterations of bone strength were not taken into consideration (Choi et al, 2013). Similarly, bone tissue and bone strength were significantly affected in murine models of pancreatic cancer (Greco et al, 2015; Zhang et al, 2015). In the present study, we showed that regardless of the type of tumor, muscle and fat loss were generally accompanied by significantly decreased BMD, while BMC was reduced exclusively in the Apc Min/+ animals (Figure 5).…”

Section: Discussionmentioning

confidence: 98%

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

et al. 2017

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Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.

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Section: Discussionmentioning

confidence: 98%

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

et al. 2017

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“…Raman bands from proline and amides (I and III), respectively, represent the contribution from collagen and the organic matrix (including collagen and noncollagenous proteins). Spectral parameters for composition analysis were determined as: collagen mineralization as indicated by mineral‐to‐collagen ratio (phosphate ν1/proline) and mineral‐to‐matrix ratio (phosphate ν2/amide III); mineral crystallinity: reciprocal of the full‐width at half‐maximum of phosphate ν1 (100×); carbonate‐to‐collagen ratio: carbonate/proline; and relative collagen content indicated by collagen‐to‐matrix ratio (proline/amide I or III) …”

Section: Methodsmentioning

confidence: 99%

Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone

Lietman

Lim

Grafe

et al. 2017

J of Bone & Mineral Res

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Osteogenesis Imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical features including low bone mass, fractures and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65KDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that Fkbp10 expression is limited to bone, tendon and ligaments in postnatal tissues. Furthermore, in both patients and Fkbp10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of Fkbp10, we conditionally ablated FKBP65 in Fkbp10fl/fl mice (Mus musculus; C57BL/6) using the osteoblast specific Col1a1 2.3kb Cre recombinase. Using μCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy of bone collagen demonstrated a decrease in mature, hydroxylysine-aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral-to-matrix ratio and in crystal size as shown by Raman spectroscopy and small angle x-ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild type littermates. Taken together, these data suggest that the altered collagen crosslinking through Fkbp10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton.

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“…Exosomal ZIP4 is associated with cancer growth and can be utilized as a diagnostic biomarker for pancreatic cancer 19 . Furthermore, silencing of ZIP4 attenuates bone loss in pancreatic cancer patients 20 . In addition, as a novel determinant of tumor invasion, ZIP4 contributes to tumor recurrence after liver transplantation in patients with hepatocellular carcinoma (HCC) 21 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ZIP4 reverses epithelial-to-mesenchymal transition and enhances the radiosensitivity in human nasopharyngeal carcinoma cells

Zeng

Liu

et al. 2019

Cell Death Dis

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ZIP4 is a zinc transporter involved in epithelial cell morphology and migration in various cancers. In the epithelial-to-mesenchymal transition (EMT), epithelial cells transition into mesenchymal cells. The EMT plays a crucial role in invasiveness and metastasis during tumorigenesis. The aim of this study was to investigate the role of ZIP4 in the invasiveness and radiosensitivity of human nasopharyngeal carcinoma (NPC). In this study, results from 99 human patients with NPC showed that ZIP4 expression levels significantly correlated with a higher TN (tumor, lymph node) classification, as well as shorter overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). Forced overexpression of ZIP4 promoted the migration and invasion of C666-1 cells through regulation of the EMT process. In contrast, ZIP4 silencing by lentivirus-mediated shRNA inhibited the EMT and metastasis of C666-1 cells in vitro and in vivo. Importantly, protein microarray analyses showed that downregulation of ZIP4 in C666-1 cells resulted in the decreased abundance of phosphoinositide 3-kinase (PI3K) p85 (Tyr607), phosphorylated (p)-Akt (Ser473), phosphorylated (p)-Akt (Thr308), and phosphorylated glycogen synthase kinase 3β (pGSK3β; Ser9). These data suggest that ZIP4 induces the EMT and promotes migration and invasion via the PI3K/Akt signaling pathway in NPC. Moreover, ZIP4 silencing significantly enhanced radiation-induced apoptosis and growth inhibition of human C666-1 cells in vitro and enhanced the antitumor activity of ionizing radiation (IR), leading to tumor growth inhibition in vivo. These results demonstrate that ZIP4 is a novel prognostic factor for malignant NPC progression. More importantly, targeting ZIP4, along with radiotherapy, may be an effective new treatment for NPC.

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ZIP4 silencing improves bone loss in pancreatic cancer

Cited by 18 publications

References 47 publications

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone

Inhibition of ZIP4 reverses epithelial-to-mesenchymal transition and enhances the radiosensitivity in human nasopharyngeal carcinoma cells

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