Circulating Long Non-Coding RNAs Act as Biomarkers for Predicting 131I Uptake and Mortality in Papillary Thyroid Cancer Patients with Lung Metastases

Long non-coding RNAs (lncRNAs), a class of non-coding transcripts, have recently been emerging with heterogeneous molecular actions, adding a new layer of complexity to generegulation networks in tumorigenesis. LncRNAs are considered important factors in several ovarian cancer histotypes, although few have been identified and characterized. Owing to their complexity and the lack of adapted molecular technology, the roles of most lncRNAs remain mysterious. Some lncRNAs have been reported to play functional roles in ovarian cancer and can be used as classifiers for personalized medicine. The intrinsic features of lncRNAs govern their various molecular mechanisms and provide a wide range of platforms to design different therapeutic strategies for treating cancer at a particular stage. Although we are only beginning to understand the functions of lncRNAs and their interactions with microRNAs (miRNAs) and proteins, the expanding literature indicates that lncRNA-miRNA interactions could be useful biomarkers and therapeutic targets for ovarian cancer. In this review, we discuss the genetic variants of lncRNAs, heterogeneous mechanisms of actions of lncRNAs in ovarian cancer tumorigenesis, and drug resistance. We also highlight the recent developments in using lncRNAs as potential prognostic and diagnostic biomarkers. Lastly, we discuss potential approaches for linking lncRNAs to future gene therapies, and highlight future directions in the field of ovarian cancer research.

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Long Non-Coding RNAs: the New Horizon of Gene Regulation in Ovarian Cancer

Worku

Bhattarai

Ayers

et al. 2017

“…Other factors are also associated with an unfavorable prognosis including age (>45 years), male sex, histology (tall cell variant histology), extrathyroidal extension (EXE), larger tumor size, stage III and IV disease, resistance to radioiodine therapy, distant metastasis, positive family history, and the BRAF V600E mutation [6, 7, 9, 13-19]. Therefore, the underlying inherent molecular mechanism of the aggressiveness and progression of PTC has great significance in the ability to understand the biological basis for the improvement in clinical outcomes [20-22]. …”

Section: Introductionmentioning

confidence: 99%

CHK2 Promotes Anoikis and is Associated with the Progression of Papillary Thyroid Cancer

Zhao

Chen

Hou

et al. 2018

Background/Aims: Cell cycle checkpoint kinase 2 (CHK2) performs essential cellular functions and might be associated with tumorigenesis and tumor progression. Here, we explored the function and molecular mechanisms of CHK2 in the progression of papillary thyroid cancer (PTC). Methods: The expression levels of both total CHK2 and activated CHK2 (p-CHK2) in tissues from 100 PTC patients were detected and evaluated using immunohistochemistry. The roles of CHK2 on cell proliferation, invasion, migration, apoptosis and cancer stem cell (CSC) markers were investigated by CCK-8, Transwell, flow cytometry, western blot and ALDEFLOUR assay. PTC cells cultured in suspension conditions were assayed for anoikis. The anchorage-independent condition was further detected by soft agar colony formation assay. Furthermore, anoikis associated regulatory proteins were explored by western blot and verified by forced downregulation experiment, respectively. Results: We found that the levels of both CHK2 and p-CHK2 were significantly upregulated in PTC cancer tissues compared with those in tumor-adjacent tissues. The overexpression of p-CHK2 in primary tumor tissues was associated with tumor aggressiveness and metastatic potential. However, the levels of both CHK2 and p-CHK2 were decreased in metastatic lymph nodes. Our results showed that CHK2 upregulated the levels of CSC markers with no effect on cell proliferation, invasion and migration. Interestingly, we revealed a previously undescribed anoikis-promoting role for CHK2 in PTC. Specifically, the detachment of PTC cells from the extracellular matrix (ECM) triggers CHK2 degradation. Then, the forced downregulation of CHK2 rescued PTC cells from anoikis, but no effect was observed on the apoptosis of adherent PTC cells. Additionally, as a novel regulator of anoikis, CHK2 can induce cell death in a p53-independent manner via the regulation of PRAS40 activation. Conclusion: High expression levels of CHK2 and p-CHK2 were associated with the progression of PTC. Our results defined an unexpected role for CHK2 as a mediator of anoikis that functions through the regulation of PRAS40 activation, which may be associated with the survival of circulating tumor cells and metastatic behavior.

“…PTC’s pathogenesis is still not fully understood [1, 2]. Existing studies suggest that radiation and genetic susceptibility contribute to the initiation and progression of PTC [6-11]. The molecularly-targeted therapy is important for better and efficient treatment of PTC [8-13].…”

Section: Introductionmentioning

confidence: 99%

The mTOR Kinase Inhibitor CZ415 Inhibits Human Papillary Thyroid Carcinoma Cell Growth

Song

et al. 2018

Background/Aim: Mammalian target of rapamycin (mTOR) plays an important role in papillary thyroid carcinoma (PTC) cell progression. CZ415 is a novel, highly-efficient and specific mTOR kinase inhibitor. The current study tested the potential anti-tumor activity of CZ415 in human PTC cells. Methods: The established (TPC-1 cell line) and primary human PTC cells were treated with CZ415. Cell survival and growth were tested by Cell Counting Kit-8 assay and BrdU ELISA assay, respectively. Cell apoptosis was tested by caspase-3/-9 activity assay, Hoechst-33342 staining assay and single-stranded DNA ELISA assay. Cell cycle progression was tested by propidium iodide-FACS assay. The mTOR signaling was tested by Western blotting assay and co-immunoprecipitation assay. The mouse xenograft tumor model was applied to study the effect of CZ415 in vivo. Results: In cultured human PTC cells, treatment with CZ415 at nM concentrations significantly inhibited cell survival and growth. CZ415 induced apoptosis activation and cell cycle arrest in human PTC cells. CZ415 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-GβL association) in TPC-1 cells, which led to de-phosphorylation of the mTORC1 substrates (S6K1 and 4E-BP1) and the mTORC2 substrate AKT (Ser-473). Further studies show that the autophagy inhibitor 3-methyladenine (3-MA) or Beclin-1 shRNA aggravated CZ415-induced cytotoxicity against PTC cells. In vivo, CZ415 oral administration inhibited TPC-1 xenograft tumor growth in mice. Conclusion: Our results show that mTOR blockage by CZ415 inhibits PTC cell growth in vitro and in vivo.