piR-39980 promotes cell proliferation, migration and invasion, and inhibits apoptosis via repression of SERPINB1 in human osteosarcoma.
在骨肉瘤中，piR-39980 通过抑制SERPINB1 促进细胞增殖、迁移和侵袭，并抑制细胞凋亡。
- 作者列表："Das B","Jain N","Mallick B
BACKGROUND INFORMATION:Piwi-interacting RNAs (piRNAs) are a novel class of ∼23-36 nts long endogenous small non-coding RNAs, earlier known to maintain germline genome integrity during development by regulating transposable elements. Recently, piRNAs are known to regulate cell proliferation, apoptosis and metastasis in different cancer cells. However, piRNAs have not yet been reported in human osteosarcoma (OS), a highly metastatic aggressive bone tumour among adolescents. Therefore, our current study aimed to decrypt the potential role of a piRNA, piR-39980 in osteosarcoma, which was earlier reported by us in fibrosarcoma, neuroblastoma and epithelial ovarian cancer. RESULTS:We found that piR-39980 is significantly upregulated in two human osteosarcoma cell lines, 143B and HOS compared to IMR90-tert fibroblast cells. The transient overexpression of endogenous piR-39980 level through transfection by piRNA mimic promotes proliferation, migration and invasion ability of OS cells, whereas its inhibition significantly induces apoptosis, chromatin condensation and γ-H2AX accumulation as well as restrains migration and invasion of OS cells. Further, we found 13 genes as targets of piR-39980 using miRanda, among which SERPINB1 that is downregulated in OS cells is seen to suppress proliferation, and migration in this cancer upon its overexpression. The knockdown of piR-39980 in OS cells led to enhanced expression of SERPINB1 indicating to be its target, which was then confirmed by dual luciferase reporter assay. In addition, gelatin zymography and western blotting revealed that transfection of piR-39980 mimic promotes MMP-2 activation, whereas its inhibition and SERPINB1 overexpression suppresses MMP-2 activation in OS cells. CONCLUSIONS:Taken together, our study revealed that piR-39980 promotes migration and invasion via MMP-2 activation as well as inhibits cell death, both through negative regulation of SERPINB1. SIGNIFICANCE:This study revealed that piR-39980 functions as an oncogene in human osteosarcoma, which could be harnessed as a potential therapeutic target for this malignancy.
背景信息: Piwi相互作用rna (piRNAs) 是一类新的 ~ 23-36 nts长的内源性小非编码rna，早先已知通过调节转座元件在发育过程中保持生殖系基因组完整性。最近，已知piRNAs在不同的癌细胞中调节细胞增殖、凋亡和转移。然而，piRNAs尚未在人骨肉瘤 (OS) 中报道，OS是一种青少年高度转移性侵袭性骨肿瘤。因此，我们目前的研究旨在解密一个piRNA，piR-39980 在骨肉瘤中的潜在作用，这是我们在纤维肉瘤，神经母细胞瘤和上皮性卵巢癌中较早报道的。 结果: 我们发现，与piR-39980 成纤维细胞相比，143B和HOS两种人成骨肉瘤细胞系中的IMR90-tert显著上调。通过转染piRNA mimic，瞬时过表达内源性piR-39980 水平，促进OS细胞的增殖、迁移和侵袭能力，而抑制其显著诱导凋亡，染色质凝聚和 γ-h2ax积累以及抑制OS细胞的迁移和侵袭。此外，我们利用miRanda发现了 13 个基因作为piR-39980 的靶点，其中在OS细胞中下调的SERPINB1 被认为在这种癌症中抑制增殖和迁移。OS细胞中piR-39980 的敲除导致SERPINB1 的表达增强，表明其是其靶点，然后通过双荧光素酶报告基因检测证实。此外，明胶酶谱和western blotting发现转染piR-39980 模拟物促进MMP-2 活化，而其抑制和SERPINB1 过表达抑制OS细胞中的MMP-2 活化。 结论: 总之，我们的研究揭示了piR-39980 通过MMP-2 激活促进迁移和侵袭，以及通过负调控serpinb1 抑制细胞死亡。 意义: 本研究揭示了piR-39980 作为一种癌基因在人骨肉瘤中发挥作用，可作为该肿瘤潜在的治疗靶点。
METHODS:OBJECTIVE:Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS: :Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS: :Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION:Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE: :This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.
METHODS:BACKGROUND:National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. METHODS:A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. RESULTS:A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. CONCLUSIONS:Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.
METHODS:PURPOSE:Low skeletal muscle mass has been associated with poor prognosis in patients with advanced lung cancer. However, little is known about the relationship between skeletal muscle mass and overall survival in patients with bone metastases from lung cancer. The objective of the present study was to evaluate the prognostic value of low trunk muscle mass in predicting overall survival in these patients. METHODS:The data from 198 patients who were diagnosed with bone metastases from lung cancer from April 2009 to May 2017 were retrospectively reviewed. The areas of the psoas and paravertebral muscles were measured at the level of the third lumbar vertebra on computed tomography scans taken at the time nearest to the diagnosis of bone metastasis. Muscle area was evaluated for male and female cohorts separately using different cutoff points. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. RESULTS:The overall survival of patients in the lowest quartile for psoas muscle area or paravertebral muscle area was significantly shorter than that of patients above the 25th percentile for muscle area (p < 0.001). Multivariate analyses showed that paravertebral muscle mass (hazard ratio, 1.73; 95% confidence interval, 1.17-2.56; p = 0.006), epidermal growth factor receptor-targeted therapy, and performance status were independent prognostic factors. CONCLUSIONS:Low paravertebral muscle mass was associated with shorter survival, independently of known prognostic factors.