Dianwen Song

MiR-126-5p regulates osteolysis formation and stromal cell proliferation in giant cell tumor through inhibition of PTHrP

Parathyroid hormone-related protein (PTHrP) has been identified to play a crucial role in osteolysis formation and stromal cell (GCTSC) proliferation in giant cell tumor (GCT). MiR-126-5p is an intronic miRNA identified as tumor suppressor in many tumors, but its role in GCT is poorly understood. We found that miR-126-5p was decreased in GCT and could directly regulate PTHrP expression. Furthermore, miR-126-5p could control osteoclast (OC) differentiation, GCTSC proliferation and osteolysis formation in GCT through negative regulation of PTHrP. Thus, these results suggest that miR-126-5p could directly target PTHrP and have a tumor suppressor function in GCT.

REGg is critical for skin carcinogenesis by modulating the Wnt/b-catenin pathway

Here we report that mice deficient for the proteasome activator, REGγ, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGγ in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGγ elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGγ promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGγ activates Wnt/β-catenin signalling by degrading GSK-3β in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of β-catenin. Conversely, MAPK/p38 inactivation or REGγ deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGγ acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/β-catenin pathway.

P50-associated COX-2 extragenic RNA (PACER) overexpression promotes proliferation and metastasis of osteosarcoma cells by activating COX-2 gene

P50-associated cyclooxygenase-2 (COX-2) extragenic RNA (PACER) is a novel long noncoding RNA that has been found to activate the COX-2 gene, which may function as an oncogene in osteosarcoma. However, the role of PACER and the relationship between PACER and COX-2 in osteosarcoma progression have been unknown until now. Here, we examined the expression levels of PACER in clinical tumor samples and human osteosarcoma cell lines, assessed the functions of PACER in osteosarcoma cell proliferation and invasion, and then explored the mechanism of PACER dysregulation in osteosarcoma. The results showed that PACER was overexpressed in osteosarcoma tissues and cell lines compared with normal tissues and osteoblasts, respectively. PACER knockdown inhibited the proliferation and invasion of human osteosarcoma cells. Downregulation of PACER significantly suppressed the expression of COX-2, and the effects of PACER on cell proliferation and invasion were rescued by COX-2 overexpression. Furthermore, COX-2 activation by PACER was NF-κB-dependent. The regulation of PACER by CCCTC-binding factor (CTCF) was associated with DNA methylation status. Taken together, these findings suggest that PACER promotes proliferation and metastasis of osteosarcoma cells by activating the COX-2 gene and its own expression was influenced by DNA methylation.

TGF-β1-induced miR-202 mediates drug resistance by inhibiting apoptosis in human osteosarcoma

PurposeA number of studies have demonstrated that microRNAs play a critical role in osteosarcoma progression, therapy and drug resistance. MicroRNA-202 has proven to be dysregulated in many human cancer studies. This study aimed to explore miR-202 contributions to drug resistance in osteosarcoma.MethodsmiR-202 expression was measured by real-time PCR in patient tissues, cell lines or cells treated with TGF-β1, using siRNA to knock down the expression of Smad2, Smad3 and Smad4. miR-202 mimics, inhibitor and scramble siRNA were transfected into osteosarcoma cells to observe effects on cell apoptosis and drug resistance. Moreover, relationships of miR-202 level with PDCD4 were investigated by luciferase reporter assay, real-time PCR and Western blotting.ResultsWe found that miR-202 is overexpressed in osteosarcoma tissues when compared with normal human osteoblasts and TGF-β1 can induce the expression of miR-202. Transfection of miR-202 mimics into osteosarcoma cell lines significantly promotes chemotherapy resistance by targeting PDCD4, a tumor suppressor which is involved in apoptosis. In contrast, transfection of miR-202 inhibitor enhances the drug sensitivity and apoptosis.ConclusionsThis study provides new insights into miRNA-202 in osteosarcoma as a potential molecular target for chemotherapy.

En Bloc Resection of Primary Malignant Bone Tumor in the Cervical Spine Based on 3-Dimensional Printing Technology.

To investigate the feasibility and safety of en bloc resection of cervical primary malignant bone tumors by a combined anterior and posterior approach based on a three‐dimensional (3‐D) printing model.

Therapeutic strategy and outcome of spine tumors in pregnancy: a report of 21 cases and literature review.

Study Design. A retrospective study was performed. Objective. To illustrate the characteristics of spine tumors during pregnancy and obtain better insight into therapeutic strategies of such tumors by analyzing 21 cases treated in Changzheng Hospital and reviewing previous reports in the literature. Summary of Background Data. The concurrence of spine tumors and pregnancy is relatively rare. There are controversies over the treatment options for this disease, which increase the difficulty of the clinical treatment. Methods. Between 2002 and 2013, 21 pregnant patients were identified with spine tumors. Clinical data including symptoms, signs, treatment options, and obstetrical and neonatal outcomes were recorded and preserved. Clinical data and treatment efficacy were analyzed via medical record review. Results. The median age of the 21 patients was 28.87 years (interquartile range, 6.00 yr). Tumor types in this series were giant cell tumor (5 cases), hemangioma (5 cases), schwannoma (4 cases), eosinophilic granuloma (2 cases), neurofibroma (1 case), multiple myeloma (1 case), and with metastatic tumor (3 cases). Two patients underwent spine surgery during pregnancy and 8 patients accepted tumor resection immediately after delivery. Pregnancy termination occurred in 5 patients, whereas the rest of the patients smoothly gave birth to healthy babies including 3 premature infants. Two patients died and 2 patients experienced local recurrence during follow-up. Conclusion. With close observation, it was found that most of pregnant patients with benign spine tumors could postpone surgery after delivery. Surgical treatment should be adopted during pregnancy when patients are with highly malignant tumor or experience a sharp deterioration and the guard of it is safer than radiotherapy and chemotherapy during pregnancy. Level of Evidence: 4

HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells

Glycolysis is a typical conduit for energy metabolism in pancreatic cancer (PC) due to the hypoxic microenviroment. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis. The aim of the present study was to explore the mechanism of interactions between hypoxia, HIF-1/2α and LDHA, and the function of LDHA on PC cells by analyzing 244 PC and paratumor specimens. It was found that LDHA was over-expressed and related to tumor stages. The result of in vitro study demonstrated that hypoxia induced LDHA expression. To explore the relationship between HIF and LDHA, chromatin immunoprecipitation assay and luciferase assay were performed. The result showed that HIF-1/2α bound to LDHA at 89bp under the hypoxic condition. Furthermore, knockdown of endogenous HIF-1α and HIF-2α decreased the LDHA expression even in the hypoxic condition, which was accompanied with a significant decrease in lactate production and glucose utilization (p < 0.01). Immunofluorescence in the 244 specimens showed that HIF-1/2α was over-expressed and associated with LDHA over-expression (p < 0.0001). Forced expression of LDHA promoted the growth and migration of PC cells, while knocking down the expression of LDHA inhibited the cell growth and migration markedly. In summary, the present study proved that HIF1/2α could activate LDHA expression in human PC cells, and high expression of LDHA promoted the growth and migration of PC cells.

HIF-1α activates hypoxia-induced BCL-9 expression in human colorectal cancer cells

B-cell CLL/lymphoma 9 protein (BCL-9), a multi-functional co-factor in Wnt signaling, induced carcinogenesis as well as promoting tumor progression, metastasis and chemo-resistance in colorectal cancer (CRC). However, the mechanisms for increased BCL-9 expression in CRC were not well understood. Here, we report that hypoxia, a hallmark of solid tumors, induced BCL-9 mRNA expression in human CRC cells. Analysis of BCL-9 promoter revealed two functional hypoxia-responsive elements (HRE-B and HRE-C) that can be specifically bound with and be transactivated by hypoxia inducible factors (HIF) -1α but not HIF-2α. Consistently, ectopic expression of HIF-1α but not HIF-2α transcriptionally induced BCL-9 expression levels in cells. Knockdown of endogenous HIF-1α but not HIF-2α by siRNA largely abolished the induction of HIF by hypoxia. Furthermore, there was a strong association of HIF-1α expression with BCL-9 expression in human CRC specimens. In summary, results from this study demonstrated that hypoxia induced BCL-9 expression in human CRC cells mainly through HIF-1α, which could be an important underlying mechanism for increased BCL-9 expression in CRC.

En bloc resection for treatment of tumor-induced osteomalacia: a case presentation and a systematic review

BackgroundTumor-induced osteomalacia (TIO) is a rare disorder, which is commonly found in craniofacial locations and in the extremities. To the best of our knowledge, only 16 cases have been described in the spine, and this is the first report to describe a case of patient with TIO in the thoracic spine combined with a mesenchymal hamartoma which had confused the therapeutic strategies to date.Case descriptionWe report the case of a 60-year-old patient with hypophosphatemia and presented with limb weakness. Treating with phosphate did not correct the hypophosphatemia and an 111In pentetreotide scintigraphy (octreotide scan) revealed an increased uptake at the right forearm. The tumor was resected totally, and the histopathology revealed a mesenchymal hamartoma, but we noticed that hypophosphatemia was not corrected after the tumor resection. Then a whole-body magnetic resonance imaging (WB-MRI) was performed and the results revealed tumorous tissues at the right T1 vertebral pedicle. The tumor was removed with an en bloc method, and the pathology showed phosphaturic mesenchymal tumor. Follow-up at 1 year after surgery revealed no recurrence, and the serum phosphorus level of the patient was normal.ConclusionsTumor-induced osteomalacia is exceedingly rare with only 16 cases in spine published in the literature. It is difficult to find and leads to years of suffering debilitating complications. In this regard, the WB-MRI is a better method to locate the real tumor. Treating with phosphate can only relieve symptoms, and a complete surgical removal remains the gold standard treatment.

XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer.

Bone metastasis occurs in approximately 30-40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis.