|Year : 2019 | Volume
| Issue : 2 | Page : 46-52
Autophagy modulation by dysregulated micrornas in human bladder cancer
Ji-Fan Lin1, Po-Chun Chen2, Thomas I-Sheng Hwang3
1 Central Laboratory; Precision Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
2 Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei; Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
3 Central Laboratory, Shine-Kong Wu Ho-Su Memorial Hospital; Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei; Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei City; Department of Urology, Taipei Medical University, Taipei, Taiwan
|Date of Submission||27-Jun-2018|
|Date of Decision||11-Aug-2018|
|Date of Acceptance||14-Nov-2018|
|Date of Web Publication||28-Mar-2019|
Thomas I-Sheng Hwang
Division of Urology, Department of Surgery, Shin.-Kong Wu Ho.-Su Memorial Hospital, Taipei 111
Source of Support: None, Conflict of Interest: None
The catabolic process of autophagy is an essential cellular function that directs the breakdown and recycling of cellular macromolecules. Increased autophagy causes various cancers, mainly bladder cancer (BC), to survive under microenvironmental stress and promotes cancer cell growth and aggressiveness. Cancer cells with rapid proliferation require a high basal level of autophagy to deal with the increased metabolic rate that generates reactive oxygen species, misfolded proteins, and damaged organelles. The regulation of autophagy by a class of small noncoding microRNAs (miRNAs) in human cancer has been discovered in recent years. In BC, a high basal level of autophagy plays critical roles in cancer survival and resistance to chemotherapy. Some studies have suggested that miRNAs participate in regulating these functions. In this review, we focused on recent key findings in the study of dysregulated miRNAs and their involvement in the regulation of autophagy in BC.
Keywords: Autophagy, beclin-1, bladder cancer, microRNA
|How to cite this article:|
Lin JF, Chen PC, Hwang TI. Autophagy modulation by dysregulated micrornas in human bladder cancer. Urol Sci 2019;30:46-52
| Introduction|| |
Bladder cancer (BC) is a major social and financial burden and is the ninth most common cancer and the thirteenth most common cause of cancer deaths worldwide. In the United States, over 79,000 new cases of BC were estimated to be diagnosed in 2017, with an estimated 16,870 deaths due to the disease. In Taiwan, BC is the ninth most common cancer among men according to the Taiwan Cancer Registry Annual Report for 2014. Currently, cystoscopy and biopsy are primary procedures used to diagnose BC. Conventional parameters, such as tumor grade, stage, and vascular and lymphatic extension, are used as prognostic indicators for BC. However, the currently used prognostic indicators have a limited ability to predict tumor recurrence, progression, metastasis, response to therapy, or survival. After the primary treatment of BC, a long-term follow-up is necessary to prevent BC recurrence. Present follow-up protocols entail the use of urethrocystoscopy, which is the gold standard, and urine cytology to detect tumor recurrence early. Ongoing surveillance generally consists of performing a cystoscopy every 3 months for 2 years, then every 6 months for 2 years, and finally annually, assuming no recurrence. The systemic treatment of BC has been limited to cisplatin-based chemotherapy. For decades, the overall survival rate of 50% at 5 years for muscle-invasive BC has not improved. The use of precision medicine and immunotherapy to treat advanced stages of BC represents a breakthrough; however, more attention should be focused on individual variations of the disease. Therefore, researchers are attempting to analyze molecular alterations that occur in BC to develop novel treatment approaches.
Autophagy means self-eating and is a ubiquitous process in eukaryotic cells; autophagy is the mechanism through which these cells respond to stress conditions and result in the digestion of the cytoplasm within lysosomes. Through autophagy, cells adapt to environmental or developmental changes. Accumulating evidence has suggested that autophagy is involved in key aspects of tumor progression such as primary tumor initiation, expansion, invasion, metastasis, and resistance to therapy. Under conditions of hypoxia and nutrient deprivation, autophagy induction provides critical building blocks and causes energy regeneration that enables the survival of tumor cells. Autophagy ensures the metabolic fitness of cancer cells during intravasation and invasion, prolongs the survival of tumor cells during tumor dormancy, and helps tumor cells to adapt to a distant tissue microenvironment during metastasis. The survival of tumor stem cells is promoted by autophagy that is induced in response to acute stresses such as chemotherapy and radiation. Therefore, autophagy provides a survival advantage to cancer cells during anticancer treatment. In 2016, we found that BC cell lines and tissues exhibited a high basal level of autophagy. Inhibition of basal autophagic activities through treatment with chloroquine or hydroxychloroquine, two well-known autophagy inhibitors, increased the apoptotic cell death of BC cells. Moreover, inhibition of drug-induced autophagy potentiated the cytotoxic effects of cisplatin and RAD001, a specific mammalian target of rapamycin (mTOR) complex 1 (mTORC1) inhibitor., Collectively, our study results demonstrated that autophagy is critical for the survival of BC cells and that either the basal or drug-induced inhibition of autophagy improves the therapeutic effects of chemotherapeutic agents against BC. Autophagy in BC is, therefore, considered to be a novel therapeutic target.
MicroRNAs (miRNAs) are a class of noncoding small RNAs that are expressed endogenously and regulate gene expression posttranscriptionally. In association with the RNA-induced silencing complex (RISC), miRNAs bind to regions located mainly within the 3′-untranslated regions of target messenger RNA (mRNA) through partial complementarity and guide the RISC to interrupt protein translation or induce mRNA degradation. miRNAs play a critical role in biological processes, such as proliferation, differentiation, stress response, and cell death, through the regulation of their targeted genes. In human cancers, miRNAs can function as a tumor suppressor or an oncogene by repressing oncogenic or tumor-suppressing mRNAs, respectively. Therefore, the regulation of tumorigenesis by miRNAs spans the phases of initiation, progression, metastasis, and treatment sensitivity. Furthermore, a single miRNA can simultaneously target a multitude of mRNA molecules and biological networks, presenting a clear advantage from a clinical point of view. Extensive research is presently focused on developing a miRNA-based therapeutic strategy for cancer treatment. For example, a recent study conducted by our group showed that several dysregulated miRNAs identified using BC tissues from Taiwanese patients regulate multiple components involved in the signaling of the insulin-like growth factor type I receptor (IGF1R) pathway. IGF1R overexpression in BC was reported to be associated with cancer-specific mortality. More recently, miR-539 was demonstrated to inhibit the proliferation and invasion of BC cells through the regulation of IGF1R. Targeting the IGF1R signaling pathway by restoring downregulated miRNAs in BC should be considered a novel approach that warrants further investigation.
miRNAs play a key role in autophagy. In this review, we summarize current studies evaluating the contribution of dysregulated miRNAs to the regulation of autophagy induction in bladder tumor samples. We analyzed aberrantly expressed BC-related miRNAs and their validated or potential target genes involved in the core autophagy pathway. In this way, we determined that multiple dysregulated miRNAs participate in every step of the autophagy process, possibly enabling the survival of cancer cells and facilitating chemotherapeutic resistance.
| The Core Autophagy Pathway and Proteins|| |
Twenty-three years after its initial discovery, the significance of autophagy was recognized with the Nobel Prize in Physiology and Medicine in 2016. Extensive research efforts have been made to expand the fundamental understanding of autophagy with respect to basic biology and human diseases such as cancer. Autophagy is an evolutionarily conserved cellular catabolic process that eliminates proteins and organelles through their delivery to lysosomes. The process of autophagy is initiated by the formation of double-membrane autophagic vacuoles (autophagosomes) in cytoplasmic components. During the last decade, many key genes and pathways involved in the process and regulation of autophagy have been identified. More than 30 genes are now identified and categorized in the autophagy-related gene (ATG) family, including ATG1, ATG4, LC3/ATG8, ATG13, and beclin-1 (BECN1). [Figure 1] illustrates how the inhibition of mTOR in mammalian cells by starvation or another stress condition leads to the activation of autophagy-initiation kinases, namely, Unc-51-like autophagy-activating kinase 1 and 2 (ULK1 and ULK2, respectively), which phosphorylate downstream ATG13 and FIP200, forming a ULK1 complex. The ULK1 complex, essential for the initiation of autophagy, is subsequently recruited to the phagophore assembly site. The class III PI3K complex constituted by BECN1, Vps34, ATG14, and AMBTA is essential for vesicle nucleation. Formation of the ATG5, ATG12, and ATG16 complex promotes the elongation of the phagophore. The LC3 ubiquitin-like conjugation system also promotes phagophore elongation. After the formation of the mature autophagosome, it fuses with the lysosome and degrades its contents.
|Figure 1: Schematic representation of the autophagy process and core autophagy protein complexes. The autophagy is a multi-step process, including induction of phagophore formation, elongation, autophagosome maturation (formation), lysosome fusion, and degradation. Following the initiation signaling or genotoxic stresses which resulted in mammalian target of rapamycin inhibition the autophagic vesicles are formed from the isolation membrane to the autophagosome and autophagolysosome (autolysosome). ULK1/2 complex that downstream of mammalian target of rapamycin mediated the early process followed by class III PI3K complex. Subsequently, LC3 processing and the nascent complex further facilitate the elongation and expansion of the phagophore to form a double membrane autophagosome. The autolysosome is formed through the fusion with lysosomes where cargo is degraded to generate amino and fatty acids for energy generation|
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| Dysregulated Micrornas in Bladder Cancer|| |
The first report concerning a set of miRNAs that are dysregulated in BC was published in 2007. The authors used a homemade oligonucleotide microchip for miRNA profiling, compared the expression of miRNAs in 27 bladder specimens that included 25 urothelial carcinomas and two normal mucosa, and found that miR-223, miR-26b, miR-221, miR-103-1, miR-185, miR-23b, miR-203, miR-17-5p, miR-23a, and miR-205 were significantly upregulated in BC. Since then, hundreds of miRNAs have been found to be downregulated, overexpressed, or otherwise aberrantly expressed in BC. The role a particular miRNA in BC is reflected in its differential expression, and the function of a particular miRNA depends on its target genes. Therefore, downregulated miRNAs that target tumor suppressor genes are considered to be onco-miRNAs, and upregulated miRNAs that target oncogenes are considered to be tumor-suppressing miRNAs. For example, a study compared 156 miRNA expression signatures among 14 BC tissues, five normal bladder urothelial samples, and three BC cell lines and found that the expression of four miRNAs (miR-30a-3p, miR-133a, miR-195, and miR-199a-3p) that usually act as tumor suppressors was downregulated in tumors. By contrast, other miRNAs, such as miR-21 and miR-200c, that are clearly upregulated in clinical BC tissues may promote the development or progression of BC., The expression profiles of miRNAs, which are detected using either microarray or deep sequencing technologies, in BC have been documented in numerous investigations by using various types of samples obtained from clinical tissue specimens, body, fluids, and BC cell lines.,, Because autophagy occurs inside cells, we focused on dysregulated miRNAs in BC tissue samples. A global review of the current literature describing the signatures of miRNAs in BC was undertaken to gain insights into how dysregulated miRNAs participate in autophagy regulation. Eighty-two articles published between January 2005 and April 2018 were retrieved by searching for the MESH terms “bladder cancer,” “miRNA,” and “review.” Review articles and their relevant references were reviewed, and we compared and summarized findings concerning miRNAs that were reported to be aberrantly expressed in BC tissues [Table 1]; miRNAs that were reported to be dysregulated in a single publication or determined to be dysregulated on the basis of BC cell lines were excluded. The results of our previous study that explored dysregulated miRNAs in samples of BC patients accorded with the results of the retrieved studies. Common dysregulated miRNAs identified in both our study and other reports are highlighted with an asterisk in [Table 1].
|Table 1: Dysregulated microRNAs detected in bladder cancer tissues reported by multiple studies|
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| Autophagy-Related Micrornas Dysregulated in Bladder Cancer|| |
Several miRNAs play critical roles in the regulation of autophagy processes such as induction, vesicle nucleation, vesicle elongation, fusion, degradation, and recycling. Some of these miRNAs are abnormally expressed in BC, and we summarize the roles of these miRNAs in the autophagy pathway in [Figure 2]. The ULK complex, including ULK1/2, ATG13, and FIP200, and its negative regulator mTORC1 are required for initiating the autophagy process. The miRNAs miR-20a and miR-106b have been reported to repress autophagic activity by targeting ULK1. Another study demonstrated that the direct effect of miR-25 on ULK1 expression makes it a novel regulator of autophagy. Furthermore, miR-26b was determined to inhibit autophagy through targeting ULK2. Finally, miR-20a was proven to negatively regulate autophagy by targeting FIP200. The miRNAs miR-15a/16 and miR-18 achieve a pro-autophagic effect by suppressing mTORC expression and have been identified as oncomiR.,
|Figure 2: Dysregulated microRNAs in BC and their roles in autophagy regulation. Various microRNAs are up-regulated (red) or down-regulated (green) in bladder cancer. These microRNAs have been reported to regulate autophagy process.(a) Autophagy induction which including ULK complex and mammalian target of rapamycin complex 1, which could be regulated by miR-20a, miR-25, miR-106a/b, miR-26, miR-18a, miR-99a and miR-15a/16. (b) Vesicle nucleation mainly involves the Beclin-1 complex, ATG2-18 complex, and ATG9. Beclin-1 itself is regulated by miR-30a and miR-17. The other regulators of this step are miR-152 and miR-199a (ATG14); miR-34a (ATG9); miR-130a (ATG2-18).(c) Vesicle elongation is controlled by LC3 and ATG12-5-16 processing systems. Several microRNAs have been reported to participate in regulation of this process. For example, miR-106b, miR-23b, miR-30a (ATG12-5-16 complex); miR-101 (ATG4); miR-204 (LC3-I); miR-423 and miR-199a (ATG3-7).(d) Fusion is a poorly defined event in mammalian cells in which some molecules participate in this process. microRNAs identified to regulate this step containing miR-101 (RAB5) and miR-194 (LAMP2). Finally, autolysosome degradation and recycling result in vesicle breakdown and cargo degradation. The beclin-1-Vps34 complex is implicated in this step, and this complex is targeted by miR-17, miR-183, miR-30a and miR-125b|
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Vesicle nucleation is the second step of autophagy and requires the activation of the Beclin-1-PI3KCIII-Vps15 complex, ATG2-18 complex, and ATG9. Several miRNAs have been demonstrated to regulate autophagy by targeting the components of this step. For example, miR-17 and miR-30a were discovered to directly target Beclin-1 and repress Beclin-1 expression, thereby disrupting vesicle nucleation., The miRNAs miR-152 and miR-199a have been reported to directly target ATG14 to modulate the activation of the Beclin-1-PI3KCIII-Vps15 complex., In addition, studies have determined that ATG2-18-9 complex activity is repressed by miR-34a and miR-130a.,
During the process of vesicle elongation and completion, numerous miRNAs participate in modulating the expression of ATG12-5-16 components such as miR-106b, miR-23b, and miR-30a.,, The other ubiquitin-like protein conjugation system responsible for vesicle elongation is LC3, and ATG4 proteins and ATG7-3 are required for LC3-II formation. A report indicated that miR-101 targets ATG4 to inhibit autophagy. The miRNAs miR-423 and miR-199a have been demonstrated to promote autophagy and regulate chemoresistance by targeting ATG7,, and miR-204 was determined to cease the activation of LC3-II, exerting a similar effect in this process.
Finally, autolysosome maturation and the cargo inside are degraded and recycled. The miRNA miR-101 was discovered to suppress RAB5, a key regulator of autolysosome fusion. Moreover, a study determined that miR-194 also plays a crucial role in autolysosome fusion by targeting LAMP2. The miRNAs miR-183 and miR-125b have been reported to target UV Radiation Resistance Associated Gene (UVRAG), which is a key component of the Beclin1-Vps34 complex and plays a central role in autolysosome maturation.,
| Future Perspective|| |
To date, novel therapeutic approaches have consisted of personalization, molecular targeting, and immunotherapy for improving survival and prognosis in BC. Numerous studies have demonstrated that aberrantly expressed miRNAs contribute to BC progression by acting as oncogenes or tumor suppressors. Recent reports have indicated that the noninvasive detection of miRNAs from body fluids, such as blood and urine of BC patients, can be used to improve diagnosis, prognosis, or even predict recurrence. Therefore, the identification of dysregulated miRNAs to develop clinical applications in BC is crucial. Autophagy is implicated in multiple steps of cancer progression, and the body of evidence concerning the dysregulation of autophagy-related miRNAs in cancer has grown considerably. Thus far, approximately 400 miRNAs have been validated as having or predicted to have interactions related to autophagy. Our previous study discovered various dysregulated miRNAs in BC, some of which play key roles in autophagy regulation. For example, our previous findings indicated that miR-99a-5p acted as a tumor suppressor through targeting mTOR in BC., Furthermore, miR-30a-5p increased drug sensitivity to cisplatin by targeting ATG5 and Beclin-1 in BC. Therefore, we forced expression of these miRNAs to improve BC treatment, and our preliminary results demonstrated a promising effect of these miRNAs in BC therapy. Additional efforts are necessary to evaluate the therapeutic roles of candidate miRNAs. Finally, future studies are necessary to further elucidate novel RNA networks in BC cells and discover miRNA information related to autophagy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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