[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Chemoresistance has long been recognized as a major obstacle in cancer therapy. Clarifying the underlying mechanism of chemoresistance would result in novel strategies to improve patient’s response to chemotherapeutics. lncRNA expression levels in gastric cancer (GC) cells was detected by quantitative real-time PCR (qPCR). MALAT1 shRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate MALAT1 expression. In vitro and in vivo assays were performed to investigate the functional role of MALAT1 in autophagy associated chemoresistance. We showed that chemoresistant GC cells had higher levels of MALAT1 and increased autophagy compared with parental cells. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 promoted autophagy in gastric cancer cells. Knockdown of MALAT1 sensitized GC cells to chemotherapeutics. MALAT1 acts as a competing endogenous RNA for miR-23b-3p and attenuates the inhibitory effect of miR-23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells. Taken together, our study revealed a novel mechanism of lncRNA-regulated autophagy-related chemoresistance in GC, casting new lights on the understanding of chemoresistance.

/pdf/long-noncoding-rna-malat1-regulates-autophagy-associated-1rdrrdtwv2.pdf

Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the second most lethal human cancer. A portion of patients with advanced HCC can significantly benefit from treatments with sorafenib, adriamycin, 5-fluorouracil and platinum drugs. However, most HCC patients eventually develop drug resistance, resulting in a poor prognosis. The mechanisms involved in HCC drug resistance are complex and inconclusive. Human transcripts without protein-coding potential are known as noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and circular RNA (circRNA). Accumulated evidences demonstrate that several deregulated miRNAs and lncRNAs are important regulators in the development of HCC drug resistance which elucidates their potential clinical implications. In this review, we summarized the detailed mechanisms by which miRNAs and lncRNAs affect HCC drug resistance. Multiple tumor-specific miRNAs and lncRNAs may serve as novel therapeutic targets and prognostic biomarkers for HCC.

/pdf/the-emerging-role-of-micrornas-and-long-noncoding-rnas-in-24pvjz8ga4.pdf

The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) can play a pivotal role in regulation of diverse cellular processes. In particular, lncRNAs can serve as master gene regulators at transcriptional and posttranscriptional levels, leading to tumorigenesis. In this review, we discuss latest developments in lncRNA-meditated gene expression at the post-transcriptional level, including gene splicing, mRNA stability, protein stability and nuclear trafficking.

Emerging roles of lncRNAs in the post-transcriptional regulation in cancer.

Considerable evidences have shown that autophagy has an important role in tumor chemoresistance. However, it is still unknown whether the lncRNA HULC (highly upregulated in liver cancer) is involved in autophagy and chemoresistance of hepatocellular carcinoma (HCC). In this study, we for the first time demonstrated that treatment with antitumor reagents such as oxaliplatin, 5-fluorouracil and pirarubicin (THP) dramatically induced HULC expression and protective autophagy. Silencing of HULC sensitized HCC cells to the three antitumor reagents via inhibiting protective autophagy. Ectopic expression of HULC elicited the autophagy of HCC cells through stabilizing silent information regulator 1 (Sirt1) protein. The investigation for the corresponding mechanism by which HULC stabilized Sirt1 revealed that HULC upregulated ubiquitin-specific peptidase 22 (USP22), leading to the decrease of ubiquitin-mediated degradation of Sirt1 protein by removing the conjugated polyubiquitin chains from Sirt1. Moreover, we found that miR-6825-5p, miR-6845-5p and miR-6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. In addition, we showed that the level of HULC was positively correlated with that of Sirt1 protein in human HCC tissues. Collectively, our data reveals that the pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents, suggesting that this pathway may be a novel target for developing sensitizing strategy to HCC chemotherapy.

LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells

HSF1 upregulates ATG4B expression and enhances epirubicin-induced protective autophagy in hepatocellular carcinoma cells

// Bo Li 1, * , Xinzhe Li 1, * , Haojun Xiong 1 , Peng Zhou 1 , Zhenhong Ni 1 , Teng Yang 1 , Yan Zhang 1 , Yijun Zeng 1 , Jintao He 2 , Fan Yang 1 , Nan Zhang 1 , Yuting Wang 1 , Yingru Zheng 3 and Fengtian He 1 1 Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China 2 Battalion 17 of Students, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China 3 Department of Obstetrics and Gynecology, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China * These authors have contributed equally to this work Correspondence to: Yingru Zheng, email: zyrdaping@aliyun.com Fengtian He, email: hefengtian06@aliyun.com Keywords: dichloroacetate, COX2, celecoxib, QKI, cervical cancer Received: February 07, 2017      Accepted: May 06, 2017      Published: June 16, 2017 ABSTRACT Dichloroacetate (DCA), a traditional mitochondria-targeting agent, has shown promising prospect as a sensitizer in fighting against malignancies including cervical cancer. But it is unclear about the effect of DCA alone on cervical tumor. Moreover, previous reports have demonstrated that the increased cyclooxygenase-2 (COX2) expression is associated with chemoresistance and poor prognosis of cervical cancer. However, it is still unknown whether COX2 can affect the sensitivity of DCA in cervical cancer cells. In this study, we found that cervical cancer cells were insensitive to DCA. Furthermore, we for the first time revealed that DCA could upregulate COX2 which impeded the chemosensitivity of DCA in cervical cancer cells. Mechanistic study showed that DCA reduced the level of RNA binding protein quaking (QKI), leading to the decay suppression of COX2 mRNA and the subsequent elevation of COX2 protein. Inhibition of COX2 using celecoxib could sensitize DCA in repressing the growth of cervical cancer cells both in vitro and in vivo . These results indicate that COX2 is a novel resistance factor of DCA, and combination of celecoxib with DCA may be beneficial to the treatment of cervical cancer.

/pdf/inhibition-of-cox2-enhances-the-chemosensitivity-of-1mybtec1ag.pdf

Nan Zhang

Papers

LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells

HSF1 upregulates ATG4B expression and enhances epirubicin-induced protective autophagy in hepatocellular carcinoma cells

Inhibition of COX2 enhances the chemosensitivity of dichloroacetate in cervical cancer cells