Sun Y-W, Chen Y-F, Li J, Huo Y-M, Liu D-J, Hua R, Zhang J-F, Liu W, Yang J-Y, Fu X-L, Yan T, Hong J, Cao H
Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China.
Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China.
Br J Cancer. 2014 Nov 25;111(11):2131-41. doi: 10.1038/bjc.2014.520. Epub 2014 Oct 14.
Invasion and metastasis are the distinct biologic characteristics of cancer, resulting in an exceptionally low 5-year survival rate in pancreatic ductal adenocarcinoma (PDAC). Understanding in detail the mechanisms underlying PDAC metastasis is critical for prevention and effective interventions. Long non-coding RNAs (lncRNAs) have been documented as having a critical role in cancer development and progression.
We examined the expression levels of lncRNA ENST00000480739 and osteosarcoma amplified-9 (OS-9) mRNA in a cohort of 35 PDAC patients. Cell proliferation, invasion and migration were examined with and without ENST00000480739 overexpression in PDAC cells.
We determined that the ENST00000480739 expression level was remarkably decreased in tumorous tissues compared with their corresponding non-tumorous tissues. The expression of ENST00000480739 was negatively associated with tumour node metastasis stage and lymph node metastasis. In addition, ENST0000048073 was an independent prognostic factor of survival time in PDAC patients following surgery. Besides, enforced expression of ENST00000480739 suppressed PDAC cells' invasion in vitro. Overexpression of ENST00000480739 significantly increased both mRNA and protein levels of OS-9, and the luciferase assays confirmed that ENST00000480739 positively regulates OS-9 by activating the transcription level of the OS-9 promoter. We further found that ENST00000480739 may target hypoxia-inducible factor-1α (HIF-1α) expression by upregulating OS-9.
These findings suggest that the frequently downregulated ENST00000480739 in PDAC contributes to tumour metastasis and progression by regulating HIF-1α. Long non-coding RNA ENST00000480739 may provide not only a therapeutic potential to suppress metastasis but it may also be a novel biomarker for risk prognostication and personal therapy screening of PDAC patients.
侵袭和转移是癌症的显著生物学特征，导致胰腺导管腺癌（PDAC）的5年生存率极低。详细了解PDAC转移的潜在机制对于预防和有效干预至关重要。长链非编码RNA（lncRNAs）已被证明在癌症发展和进展中起关键作用。
我们检测了35例PDAC患者队列中lncRNA ENST00000480739和骨肉瘤扩增9（OS-9）mRNA的表达水平。在PDAC细胞中过表达和未过表达ENST00000480739的情况下，检测细胞增殖、侵袭和迁移情况。
我们确定，与相应的非肿瘤组织相比，肿瘤组织中ENST00000480739的表达水平显著降低。ENST00000480739的表达与肿瘤结节转移分期和淋巴结转移呈负相关。此外，ENST0000048073是PDAC患者术后生存时间的独立预后因素。此外，ENST00000480739的强制表达抑制了PDAC细胞的体外侵袭。ENST00000480739的过表达显著增加了OS-9的mRNA和蛋白水平，荧光素酶检测证实ENST00000480739通过激活OS-9启动子的转录水平正向调节OS-9。我们进一步发现，ENST00000480739可能通过上调OS-9靶向缺氧诱导因子-1α（HIF-1α）的表达。
这些发现表明，PDAC中经常下调的ENST00000480739通过调节HIF-1α促进肿瘤转移和进展。长链非编码RNA ENST00000480739不仅可能提供抑制转移的治疗潜力，还可能是PDAC患者风险预后和个体化治疗筛查的新型生物标志物。
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