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Abstract

Cholangiocarcinoma (CCA) is one of the most aggressive malignancies with increasing worldwide incidence and is characterized by unfavorable prognosis due to its early invasive characteristics and poor response to chemotherapy or radiotherapy. Accumulating evidence has indicated that aberrantly expressed circular RNAs (circRNAs) are involved in cancer development and progression. However, their clinical values and biological roles in CCA remain unclear. Hsa_circ_0001649, a novel cancer-related circRNA, has been previously reported to be downregulated in hepatocellular carcinoma and gastric cancer. In the present study, qRT-PCR was carried out to measure the expression of hsa_circ_0001649 in CCA tissue samples and cell lines, and the correlation between hsa_circ_0001649 expression and clinicopathologic features was analyzed. The biological functions of hsa_circ_0001649 in CCA cells were evaluated both in vitro and in vivo. As a result, hsa_circ_0001649 was aberrantly downregulated in CCA tissues and cells, and this downregulation was associated with tumor size and differentiation grade in CCA. In addition, hsa_circ_0001649 overexpression caused tumor suppressive effects via inhibiting cell proliferation, migration and invasion; inducing cell apoptosis in KMBC and Huh-28 cells. On the contrary, silencing of hsa_circ_0001649 caused the opposite phenotypes. Furthermore, tumor xenograft study confirmed the in vitro results. Collectively, our findings suggest that hsa_circ_0001649 might be a rational CCA-related therapeutic target. (C) 2018 Elsevier Inc. All rights reserved.

Authors

Xu, Yi;  Yao, Yue;  Zhong, Xiangyu;  Leng, Kaiming;  Qin, Wei;  Qu, Lijun;  Cui, Yunfu;  Jiang, Xingming

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  • In this study, Xu and co-workers analyzed the role of circular RNA (circRNA) in cholangiocarcinoma (CCA). The authors specifically evaluated the expression of the circRNA circ-0001649 (a.k.a circSHPRH). A comprehensive analysis has been carried out showing a decreased expression of circ-0001649 in both CCA cell lines and tissues. Gain and loss of function approaches were performed in order to better understand the molecular mechanisms regulated by circ-0001649. Thus, the authors reported that the inhibition of circ-0001649 expression positively regulates CCA cells migration, invasion and proliferation and attenuates apoptosis of CCA cell lines. Interestingly, the tumor-suppressive action of circ-0001649 was also assessed in vivo on mouse xenograft models. Overall, this manuscript provides some interesting information. However, the whole study in the present form is simple and descriptive and needs further investigation to get a better insight into the regulatory functions of circ-0001649. I have some suggestions that if properly addressed may increase the significance and overall message of this otherwise commendable study.

    1- In the introductory section, the rationale of studying specifically circ-0001649 in CCA should be better clarified.

    2- In the method section, it should better clarified whether the term non-tumorous tissues designate normal liver cancer tissues or normal cholangiocytes. In this instance, normal cholangiocytes are the most relevant control.

    3- In the method section, the quantification method for circRNA should be further detailed. Notably, the authors should precise whether they enriched their total RNA pool in circRNA by degrading linear RNA through RNAse treatment.

    4- It is well established that multiple circRNA isoforms are produced from the same parental transcript. It is not clear whether or not the pair of divergent primers used for circ-0001649 can amplify additional isoforms. Authors should provide the method used to isolate this specific isoform and subsequently sequence it (Fig. 1).

    5- CircRNA are well-known for their capability to sponge miRNA, acting as competitive endogenous RNA preventing them to bind their natural targets. Therefore, a full mechanistic part could have been added to identify the tumor suppressive miRNA sponged by circ-0001649. Additionally, the miRNA targets dysregulated by the overexpression or the inhibition of circ-0001649 could have been identified by WB analyses.

    6- It would have been valuable to associate circ-0001649 expression with additional clinical features, such as overall survival and relapse free survival.

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  • Abstract, title and references ● Is the aim clear? Yes ● Is it clear what the study found and how they did it? Yes ● Is the title informative and relevant? Yes ● Are the references: ● Relevant? Yes ● Recent? Yes ● Referenced correctly? Yes ● Are appropriate key studies included? Yes Introduction/ background ● Is it clear what is already known about this topic? Yes ● Is the research question clearly outlined? Yes ● Is the research question justified given what is already known about the topic? Yes Methods ● Is the process of subject selection clear? Yes ● Are the variables defined and measured appropriately? Yes ● Are the study methods valid and reliable? To some Extent ● Is there enough detail in order to replicate the study? Yes Results ● Is the data presented in an appropriate way? Yes ● Tables and figures relevant and clearly presented? Yes ● Appropriate units, rounding, and number of decimals? Yes ● Titles, columns, and rows labelled correctly and clearly? Yes ● Categories grouped appropriately? Yes ● Does the text in the results add to the data or is it repetitive? repetitive ● Are you clear about what is a statistically significant result? Yes ● Are you clear about what is a practically meaningful result? Yes Discussion and Conclusions ● Are the results discussed from multiple angles and placed into context without being over interpreted? Yes ● Do the conclusions answer the aims of the study? To some extent ● Are the conclusions supported by references or results? Yes ● Are the limitations of the study fatal or are they opportunities to inform future research? Needs Future Research.

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