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Review

Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer

by
Xueni Yang
1,
Shizheng Xiong
1,
Xinmiao Zhao
1,
Jiaming Jin
1,
Xinbing Yang
2,
Yajing Du
2,
Linjie Zhao
1,
Zhiheng He
1,
Chengjun Gong
1,
Li Guo
1,* and
Tingming Liang
2,*
1
State Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, Nanjing 210023, China
2
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(3), 1561; https://doi.org/10.3390/ijms25031561
Submission received: 15 November 2023 / Revised: 15 December 2023 / Accepted: 22 January 2024 / Published: 26 January 2024
(This article belongs to the Special Issue Exosomes and Non-coding RNA Research in Health and Disease)
Browse Figures
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Abstract

:
Autophagy, a complex and highly regulated cellular process, is critical for the maintenance of cellular homeostasis by lysosomal degradation of cellular debris, intracellular pathogens, and dysfunctional organelles. It has become an interesting and attractive topic in cancer because of its dual role as a tumor suppressor and cell survival mechanism. As a highly conserved pathway, autophagy is strictly regulated by diverse non-coding RNAs (ncRNAs), ranging from short and flexible miRNAs to lncRNAs and even circRNAs, which largely contribute to autophagy regulatory networks via complex RNA interactions. The potential roles of RNA interactions during autophagy, especially in cancer procession and further anticancer treatment, will aid our understanding of related RNAs in autophagy in tumorigenesis and cancer treatment. Herein, we mainly summarized autophagy-related mRNAs and ncRNAs, also providing RNA–RNA interactions and their potential roles in cancer prognosis, which may deepen our understanding of the relationships between various RNAs during autophagy and provide new insights into autophagy-related therapeutic strategies in personalized medicine.

1. Introduction

The process of autophagy can effectively remove nutrients from cells and has been shown to inhibit cancer development [1,2]. By removing damaged proteins and organelles, autophagy can also limit oxidative stress and suppress oncogenic signals, further highlighting its potential significance in cancer [3,4,5,6,7]. Autophagy can have both positive and negative effects on the development of tumors, promoting the death of tumor cells and preventing the occurrence of tumors. It can also provide energy for cancer cells when they are under stress [8]. However, as the tumor progresses, tumor cells utilize autophagy in diverse ways to combat nutrient scarcity and hypoxia [9]. Regulating autophagy can promote cancer cell proliferation, but it can also help inhibit the expression of oncogenes. Decreased and abnormal autophagy inhibits the degradation of damaged components or proteins in oxidative stress cells, leading to cancer development [10]. Some autophagy-related genes (ATGs), such as ATG2B, ATG5, ATG9B, and ATG12, have been reported to contain frameshift mutations in cancer [11,12], implicating the potential contributions to tumorigenesis and cancer metastasis.
Both autophagy-related genes and non-coding RNAs (ncRNAs) are involved in the autophagy process, mainly including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Some genes have been used to treat patients in dozens of clinical trials aimed at regulating autophagy to treat or prevent diseases [13]. By directly suppressing DACT3 in cancer cells, miR-638 can promote autophagy and malignant phenotypes [14], lncRNA MALAT1 may contribute to gastric cancer progression via inhibiting autophagic flux [15], and exosomal circ_0091741 can promote cell autophagy through the miR-330-3p/TRIM14/DvI2/Wnt/beta-catenin axis [16]. Some ncRNAs have been observed to participate in the regulation of autophagy, either by inducing or inhibiting it, leading to the modulation of cancer [17]. These diverse ncRNAs play a key role in cancer cell homeostasis and cancer progression by regulating autophagy. Clarifying the relationship between autophagy and ncRNAs will contribute to elucidating a promising potential therapeutic target in cancer treatment. Indeed, different types of ncRNAs can either promote or inhibit autophagy, which may, in turn, affect the migration of cancer cells [18]. The discovery of ncRNAs in autophagy has opened up new possibilities for understanding important biological processes. The expression and potential biological roles of ncRNAs have a significant impact on the level of cellular autophagy during different physiological and pathological stages, which may contribute to providing new insights for the diagnosis and treatment of cancer.
In order to shed light on the intricate relationships between autophagy-related genes, ncRNAs, and their potential impact on disease pathology, we mainly summarized autophagy-related pathways and RNAs, together with their biological function in pathological processes, especially the potential roles in cancer prognosis and treatment. Then, RNA interactions were further discussed, aiming to understand the possible regulatory network between various RNAs during autophagy, as well as their potential roles in autophagy-related therapeutic strategies. A profound understanding of the autophagy-related RNA regulatory network may contribute to clinical application in cancer diagnosis, classification, and treatment.

2. Autophagy-Related Genes and Cancer

Autophagy is typically divided into distinct stages: initiation, vesicle nucleation, vesicle elongation, vesicle fusion, and cargo degradation [19] (Figure 1). The first stage involves the induction of autophagy under stress, such as starvation and hypoxia. In the second stage, the PI3K complex initiates vesicle nucleation, and the third stage consists of autophagic membrane elongation and completion, which are regulated by two systems, the ATG12-ATG5-ATG16L and ATG8 (MAP1LC3 or LC3 in mammals) systems [20]. The autophagosome fuses with the lysosome and is then degraded, and the macromolecules are reused to fuel relevant metabolic pathways. The biological process of autophagy serves a vital function in breaking down proteins and organelles to prevent the buildup of harmful waste and maintain the proper functioning of cells and organisms [21,22]. It effectively removes misfolded proteins and damaged organelles [23] and can promote survival in nutrient-deficient environments [24]. Without its crucial role, abnormal cell function, reactive oxygen species (ROS) imbalances, inflammation, and antigen presentation defects could occur [25]. Thus, the cells are prone to malignant transformation into tumor cells. Autophagy plays an important role in both tumor suppression and tumor promotion, and mice with systemic mosaic deletion of Atg5 and liver-specific Atg7−/− can develop benign liver adenomas [26].
It is generally accepted that autophagy can inhibit the growth and development of tumor cells. In some cases, autophagy can promote tumor suppression by removing specific factors, such as p62 and p53, and elevated levels of p62, found in many cancer types, are thought to promote tumors [27], while the deficiency of p53 accelerates pancreatic tumor progression [28]. Some genes are identified as autophagy-related genes at different stages (Table 1), such as the MTORC1 protein, which senses nutrients acting as a suppressor of autophagy. NCAPD2 can restrict autophagy by regulating the Ca2+/CAMKK2/AMPK/mTORC1 pathway, thereby promoting colorectal cancer [29]. Meanwhile, AMPK is activated during instances of energy deprivation and encourages autophagy, which fosters the formation of dormant polyploid giant cancer cells [30]. Autophagy is heightened in hypoxic regions of tumors, which are vital for the survival of cancer cells. The removal of the BECN1 gene (Beclin-1) increases the likelihood of postpartum breast tumor occurrence [31]. The deliberate suppression or removal of critical autophagy genes in cancer cells has been shown to decrease their ability to survive and form tumors, and the activation of tumor pathways and stress in the tumor microenvironment may increase the need for autophagy to aid in tumor growth and survival. Based on its critical roles in multiple biological processes, autophagy has a global role in metabolism, protein and organelle quality control, and the relationship between autophagy and anti-tumor immune response will enrich the relevant studies, especially in cancer treatment. A better understanding of how cancer cells overcome the inhibitory effects of autophagy to progress, as well as how autophagy maintains established survival, is crucial. The regulation of autophagy is quite complex in tumorigenesis and cancer progression, and the detailed molecular mechanism and possible clinical application in anticancer therapeutic strategies remain a challenge.
As a natural and complex cellular process, multiple signaling pathways are involved in the physiological process of autophagy, such as the PI3K-AKT-mTOR and MAPK-Erk1/2 pathways. The PI3K/protein kinase B(AKT)/mTOR signaling pathway, which inhibits autophagy in conditions of nutrient enrichment, is activated when PI3K binds to growth factor receptors. AKT is activated, in turn activating mTOR. However, PTEN can antagonize PI3K activity, thereby inhibiting AKT activity and mTOR activation, and then inducing autophagy [32]. Upstream signals of the autophagy signaling pathway are mainly involved in the mammalian target of the rapamycin (mTOR)-dependent pathway and mTOR-independent pathway, such as AMP-activated protein kinase (AMPK), PI3K, Ras-MAPK, p53, PTEN, and endoplasmic reticulum stress [33]. The process of autophagy induction relies heavily on mTOR kinase. Autophagy is inhibited by the activation of mTOR pathways, such as the AKT, MAPK, PI3K-I/Akt and MAPK/Erk1/2 signaling pathways, while it is promoted by the negative regulation of mTOR pathways. ULK is a key autophagy core protein with serine/threonine kinase activity. The activation of the ULK complex in autophagic signaling, including ULK1 or ULK2, FIP200, and ATG13, occurs prior to autolysosome assembly [34]. The ULK1 complex serves as a bridge in vivo, connecting the upstream nutrient or energy sensors mTOR and AMPK with the formation of downstream autophagosomes. The phosphorylation of ULK1 has long been recognized as a critical regulator of autophagy. Recently, two kinases, AMPK and mTOR, have been discovered to catalyze the phosphorylation of ULK1 [35], which may play a pivotal role in autophagy. In the presence of adequate nutrition, when AMPK is inactivated, mTOR can bind to ULK1 serine 757, leading to the inhibition of ULK1–AMPK interaction, inactivation of ULK1, and, ultimately, the cessation of autophagy signaling. There are both positive and negative links between apoptosis and autophagy, and there is extensive signal “talk” between the two processes. When nutrients are deficient, autophagy functions to promote cell survival, but excessive autophagy can lead to autophagic cell death, which is morphologically distinct from apoptosis. Autophagy-related genes may be potential drug targets via involvement in apoptosis regulation and PI3K/MTOR signaling pathways (Figure 2A) [36], implying their potential clinical application in cancer treatment [37]. These genes always show dynamic expression patterns in different cancer types (Figure 2B,C), and abnormal expression patterns imply that these genes may be critical in cancer tumorigenesis and metastasis [38]. For example, LAMP3 is detected with higher expression pattern in some cancers, and overexpression may play a role in tumorigenesis. Patients with higher or lower expression of specific genes may have better survival (Figure 2D), suggesting potential roles for these genes in cancer prognosis [39].

3. Regulation Roles of ncRNAs in Autophagy

Many autophagy-related genes may be directly or indirectly regulated by diverse ncRNAs (Figure 1), demonstrating complex RNA interactions during the essential stages of autophagy, including autophagy initiation, vesicle nucleation, autophagosome elongation, autophagosome formation, and maturation [10]. They are also involved in regulating the upstream signaling pathways that control autophagy induction. Some ncRNAs can directly regulate genes related to autophagy and are known to have significant impacts on various stages of the process and cancer development. Numerous human diseases, ranging from cancer and neurodegeneration to metabolic disorders such as diabetes and organ-related ailments such as heart, lung, liver, kidney, and stomach issues, have been linked to autophagy dysfunction that may be involved in the regulatory roles of ncRNAs (Table 2, Table 3 and Table 4).

3.1. Regulation of ncRNAs in Autophagy Initiation

Autophagy in higher mammals is mainly triggered by ULK complexes and facilitated by AMPK, AKT, mTOR, ULK complex, etc. NcRNAs primarily control the process of autophagy induction by regulating these compounds, such as factors that affect cancer cell migration. Understanding the role of ncRNAs in regulating autophagy in diseases will provide new strategies for the clinical treatment of various autophagy-related diseases.
NcRNAs can influence the initiation phase of autophagy in human cancer by regulating the expression of various components in the ULK complex, which is a key autophagy core protein during the initiation of autophagy. For example, miR-17 family members, miR-20a and miR-106b, may regulate autophagy induced by leucine deprivation in C2C12 myoblasts by inhibiting ULK1 expression [53]. It has been confirmed that other members of the miR-17 family, namely miR-20b, miR-106a, miR-93, and miR-17-5p, also inhibit the expression of ULK1, which in turn inhibits autophagy [44]. Autophagy protects lung adenocarcinoma cells by decreasing ULK1 expression via the miR-106a-ULK1 axis [45]. Other miRNAs, including miR-489, miR-142-5p, and miR-25, can affect autophagy by targeting ULK1 [46,47,48]. ULK2 is regulated by miR-885-3p, suggesting that miR-885-3p might contribute to the regulation of squamous cell carcinoma cell autophagy and/or apoptosis upon cisplatin exposure [51]. Furthermore, lncRNA SNHG6 is able to promote colorectal cancer chemoresistance and enhance autophagy through regulation of ULK1 by sponging miR-26a-5p [79]. Knockdown of lncRNA AK044604 (regulator of insulin sensitivity and autophagy, RISA), a regulatory factor, regulates insulin sensitivity and autophagy in mice, increases the phosphorylation of ULK1, and thus helps initiate autophagy and weaken insulin resistance [106]. Circ_0009910 has been found to regulate the expression of ULK1 by sponging miR-34a-5p in chronic myeloid leukemia, thereby activating the level of autophagy [96], and circ_CDYL accelerates autophagic flux via sponging miR-1275 and regulating the expression of autophagy-related genes ATG7 and ULK1, thus promoting autophagy and the progression of breast cancer [97]. ATG13 can be regulated by miR-133a-3p, and FIP200 can be simultaneously regulated by several miRNAs, including miR-20a, miR-20b, miR-224-3p, and miR-309-3p [52]. In addition, circMUC16 can directly associate with ATG13, stabilize its expression, and then promote autophagy in epithelial ovarian cancer by regulating Beclin1, RUNX1, and ATG13 [101].
mTOR plays an important role in the initiation of cell autophagy and can be promoted via activated AKT. The miR-99 family, comprising miR-99a, miR-99b, and miR-100, can indirectly promote autophagy by inhibiting the IGF-1R/AKT/mTOR signaling pathway, while miR-100 can inhibit mTOR and then activate autophagy [54]. miR-378 promotes autophagy initiation through the mTOR/ULK1 axis and sustains autophagy via FoxO-mediated transcriptional reinforcement [76]. LncRNAs can also regulate autophagy by directly or indirectly affecting mTOR molecules. For example, overexpression of NBR2 can inhibit the mTOR pathway and AMPK is activated, boosting AMPK levels in colorectal cancer under energy stress [77]. LncRNA H9 plays an important role in p38/AMPK/mTOR, toll-like receptor, and autophagic activation [107], and overexpression of lncRNA PTENP1 indirectly inhibits the PI3K/AKT pathway through PTEN overexpression and then induces pro-death autophagy, leading to the death of hepatocellular carcinoma cells [84,85]. In esophageal squamous cell carcinoma, circRNA ciRS-7 affects the epidermal growth factor receptor AKT-mTOR signaling pathway, thus inhibiting the autophagy of ESCC cells [100].

3.2. Regulation of ncRNAs in Vesicle Nucleation

During vesicle nucleation, proteins and liposomes combine to form double-membrane binding vesicles, known as autophagosomes. This process is mainly initiated by a complex of autophagy-related proteins called the class III phosphatidylinositol 3-kinase (PI3K) complex. Diverse ncRNAs have powerful regulatory versus control roles during the vesicle nucleation stage.
Beclin-1, one of the key molecules of autophagosome nucleation, is a critical target for regulating autophagy, and may play a key role in whether cells eventually go to autophagy or apoptosis. Several miRNAs, including miR-124-3p, miR-216b, miR-376b, miR-409-3p, and members of the miR-30 family, have been reported to affect the expression of Beclin-1 and autophagy by targeting the 3′-UTR of Beclin-1 [58]. miR-30a targets Beclin-1, which mediates autophagy [58], and inhibits autophagy by downregulating the expression of Beclin-1 in medulloblastoma [59]. miR-216b can inhibit cisplatin sensitivity of non-small cell lung cancer through regulating apoptosis and autophagy via miR-216b/Beclin-1 pathway [63], and miR-143 plays an essential role in tumorigenesis and chemotherapy resistance by targeting the various cellular and molecular pathways (i.e., PI3K/AKT/Wnt, EMT, p53, and ATM) involved in the autophagy pathways pathogenesis of colorectal cancer [65]. Downregulation of lncRNA MALAT1 attenuates neuronal cell death through suppressing Beclin1-dependent autophagy by regulating miR-30a expression in cerebral ischemic stroke [108]. The expression of lncRNA SNHG12 is upregulated in mouse MCAO models and OGD/R models in SH-SY5Y cells, promoting LC3-II and Beclin-1 expression levels and thus inducing autophagy activation [86]. CircRNF144B promotes the ubiquitination of Beclin-1 by sponging injection of miR-11-342p, thereby inhibiting autophagic flux and promoting ovarian cancer progression [109]. In epithelial ovarian cancer, circMUC16 can promote the expression of Beclin-1 and Runx1 by sponging miR-199a-5p, thus promoting autophagy [101].
ATG7, ATG14, and the Vps34 complex also play an important role in the process of autophagosome nucleation. Overexpression of lncRNA PVT1 increases the expression levels of ATG7, which is essential for autophagy initiation and the formation of a double-membrane structure, thus inducing autophagy [110]. LncRNA BCRP3 is a positive regulator of autophagy, mostly found in the cytoplasm, which binds to the Vps34 complex to enhance its enzymatic activity [111]. PVT1 interacts with ATG14 in the cytoplasm and can upregulate the expression of ATG14 and thus regulate autophagic activity [88].

3.3. Regulation of ncRNAs in Autophagic Vesicle Elongation

ATG12 is driven by ATG7 (an E1-like enzyme) and ATG10 (an E2-like enzyme), conjugates with ATG5, and then interacts with ATG16 (mammalian orthologous ATG16L) to form the ATG12–ATG5–ATG16 complex. LC3 is then converted from its cytoplasmic-soluble isoform (LC3-I) to its membrane-anchored isoform (LC3-II) by the ATG12-ATG5-ATG16 complex, together with ATG7 and ATG3 (an E2-like enzyme). ATG12, ATG5, and ATG16 participate in the elongation of the autophagic vesicle [112].
miR-214 significantly increases the radiosensitivity of colorectal cancer via the inhibition of autophagy and induction of apoptosis by targeting ATG12 [71]. ATG12 is also a target of circPOFUT1 in regulating autophagy-related chemical resistance, and circPOFUT1 promotes ATG12 expression to regulate autophagy-associated chemoresistance by sponging miR-488-3p in gastric cancer [102]. miR-106a and miR-106b, two members of the miR-17 family, have been shown to inhibit starvation-induced autophagy in colorectal cancer cells, while only miR-106b inhibits starvation-induced autophagy by inhibiting the expression of ATG16L1 [72]. Autophagy inhibition occurs when important genes, such as ATG16L1 and ATG12, are targeted. LncRNA CCAT1 facilitates hepatocellular carcinoma cell autophagy and cell proliferation by functioning as a sponge for miR-181a-5p and then regulating ATG7 expression [91]. Interference with lncRNA SNHG3 improves brain I/R injury by downregulating ATG7 to restrain autophagy [113]. The inflammation-induced ectopic expression of lncRNA TGFB2-OT1 activates autophagy via increasing the expression levels of ATG13, ATG3, ATG7, and P62, and the small molecule inhibitor 3BDO significantly decreases TGFB2-OT1 levels and inhibits subsequent autophagy and inflammation [114]. LncRNA HNF1A-AS1, sponging miR-30b from binding to its target of ATG5, provokes autophagy in hepatocellular carcinoma. Moreover, Beclin-1 and ATG12 have also been defined as targets of miR-30b, indicating that HNF1A-AS1 upregulates Beclin-1, ATG5 and ATG12 expression to promote elongation of the autophagic vesicle [93,115]. Circ_0092276 can repress ATG7 via sponging miR-384, thus effecting autophagy and proliferation as well as repressing apoptosis of breast cancer cells [103].
During autophagic vesicle elongation, the LC3 protein is cleaved by ATG4 at its carboxyl terminus immediately after synthesis, resulting in the production of LC3-I localized in the cytoplasm. LncRNA NEAT1 can induce abnormal autophagy by stabilizing PINK1, which is an LC3-II upstream regulatory factor and plays a role in the pathogenesis of Parkinson’s disease [90]. In epithelial ovarian carcinoma, overexpression of HULC reduces ATG7, LC3-II and LAMP1 expression while inducing SQSTM1 (P62) and ITGB1 expression, thus inducing cell proliferation, reducing apoptosis, and inhibiting autophagy in vitro [95]. In drug-resistant renal clear cell carcinoma cells treated with gemcitabine, when circ_0035483 expression is downregulated, the LC3-II/LC3-I ratio is significantly reduced, thus inhibiting autophagy [104]. Hsa_circ_0092276 overexpression effects the proliferation of breast cancer cells, while hsa_circ_0092276 silencing represses the expression of LC3-II/LC3-I and Beclin-1 [103]. These diverse ncRNAs contribute to autophagic vesicle elongation via direct or indirect interactions with critical autophagy-related genes, and their important regulatory roles also provide the possibility of discovering potential drug targets in cancer treatment.

3.4. Regulation of ncRNAs in Autophagosome Formation and Maturation

ATG7 and ATG16L1 also play important roles in the process of autophagosome formation. They are upregulated in the neurons and promote autophagosome formation. Overexpression of miR-96 significantly prevents brain damage in SE rats by inhibiting ATG7 and ATG16L1 expression and autophagosome formation in the hippocampus [116]. Circ_PABPN1 competitively binds HuR, blocks its binding to ATG16L1, inhibits ATG16L1 translation, and thus regulates autophagy in intestinal epithelial cells [105]. In intestinal epithelial cells, the targeted deletion of HuR specifically reduces the level of ATG16L1 in the intestinal mucosa, while circPABPN1 can bind to HuR to enhance autophagy [105]. LncRNA 17A knockdown increases the expression levels of LC3-II, which is a hallmark of autophagosome formation [117]. The expression of LC3, P62, and LAMP2 can be regulated by lncRNA MALAT1, which represses autolysosome fusion via the downregulation of LAMP1 and LAMP2, leading to autophagic inhibition [118].
The autophagosome maturation process requires several complexes, including integral lysosomal proteins (such as LAMP1, LAMP2, and LAMP3) and RAB proteins (such as RAB5 and RAB7), to aid in autophagosome–lysosome fusion and maturation [119,120]. miR-138-5p contributes to this process via targeting SIRT1 to inhibit autophagy in pancreatic cancer by indirectly regulating RAB7 [73]. miR-487b-5p directly targets LAMP2, affecting autophagy in cortical neurons [74], and miR-207 and miR-352 can affect autophagy by directly targeting LAMP2 in ischemic stroke [121]. miR-224, miR-21, miR-373-5p, and miR-379 can interact with LAMP2, regulating its expression [122,123]. Additionally, miR-205 inhibits autophagy by targeting RAB27A and LAMP3, leading to increased cisplatin cytotoxicity in prostate cancer cells [75]. Certain miRNAs are capable of targeting multiple proteins at different stages of autophagy. Specifically, miR-33a-5p and miR-33a-3p can directly target ATG5, ATG12, LC3B, and LAMP1 [124], and these miRNAs can also inhibit AMPK-dependent autophagic activation and lysosomal gene transcription by targeting FOXO3 and TFEB. Hsa_circ_0001658 suppresses the autophagy of gastric cancer cells via the miR-182/RAB10 axis and sponges miR-182 to suppress the expression of RAB10 [125].
Taken together, diverse ncRNAs have been found to play a significant role in the autophagy process, which involves the breakdown and recycling of cellular components, implicating the potential complex interaction network among different RNAs, especially via ceRNA networks (Figure 3). Some lncRNAs and circRNAs may act as miRNA sponges to perturb the miRNA regulatory network and then disturb the expression levels of target mRNAs, although many ncRNAs also can regulate mRNA expression via binding target mRNAs as important regulators. As a critical interaction method, ceRNA networks have been widely studied because the RNA interactions among different RNAs may contribute to multiple biological processes, even in tumorigenesis. According to autophagy-related RNAs, several genes are involved in different ceRNA networks, such as ATG7, mTOR, and ULK1 (Figure 3), indicating that these autophagy-related genes are prone to be strictly regulated by multiple ncRNAs via a complex RNA interaction. The dysregulation of ncRNAs or genes may contribute to metabolic disorders, neurodegenerative disorders, and cancer. The intricate relationships between RNAs during autophagy should be further considered to reveal their potential roles in cancer prognosis and treatment.

4. Conclusions and Perspective

Autophagy plays a dual role in cancer, and it is crucial to gain a better understanding of how tumors overcome autophagy’s growth-inhibiting effects to promote tumor development while maintaining or restoring autophagy to sustain established tumors. Diverse ncRNAs contribute to autophagy as regulators via RNA interactions, especially via a ceRNA regulatory network that has been widely considered as a potential biomarker for cancer diagnosis and prognosis. As a class of pivotal regulators, ncRNAs have spatiotemporal specificity and tissue specificity, indicating that they may be potential biomarkers and therapeutic targets for autophagy-related diseases. Based on the important regulatory roles of ncRNAs in a coding-non-coding RNA interaction network, the regulatory network containing various RNAs is more complex than we previously thought, and the detailed interaction mechanism may provide novel strategies for autophagy-related diseases, particularly for cancer. Although many ncRNAs have been reported as critical regulators, more ncRNAs may contribute to autophagy process via direct or indirect interactions with autophagy-related genes, and the detailed ncRNA–mRNA interaction profile should be explored to systematically understand autophagy-associated regulatory networks. It is encouraging that the interactions of different autophagy-associated RNAs may be combined with traditional chemotherapy or anti-tumor immune response strategies to potentially benefit cancer patients.

Author Contributions

Conceptualization: L.G. and T.L.; Acquisition, analysis, or interpretation of data: X.Y. (Xueni Yang), S.X., X.Z., J.J., X.Y. (Xinbing Yang), Y.D., L.Z., Z.H. and C.G.; Writing—original draft preparation: L.G., X.Y. (Xueni Yang) and T.L.; Writing—review and editing: L.G. and T.L.; Supervision: T.L.; Funding acquisition: L.G. and T.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (No. 62171236), the key project of social development in Jiangsu Province (No. BE2022799), the key projects of Natural Science Research in Universities of Jiangsu Province (No. 22KJA180006), the Open Research Fund of State Key Laboratory of Bioelectronics, Southeast University (SKLB2022-K03), with funding from the Shandong Provincial Key Laboratory of Biophysics and the Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD).

Acknowledgments

We Thanks for Jiafeng Yu in the collection and confirmation of literature on autophagy-related genes and the suggestion on the revision editing.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. A simple model contains some autophagy-related genes and ncRNAs using Figdraw to indicate the interactions of autophagy-related genes and ncRNAs. Autophagy-related genes can be regulated by ncRNAs, and some lncRNAs and circRNAs may act as miRNA sponges to perturb gene expression.
Figure 1. A simple model contains some autophagy-related genes and ncRNAs using Figdraw to indicate the interactions of autophagy-related genes and ncRNAs. Autophagy-related genes can be regulated by ncRNAs, and some lncRNAs and circRNAs may act as miRNA sponges to perturb gene expression.
Ijms 25 01561 g001
Ijms 25 01561 g002aIjms 25 01561 g002b
Figure 2. Autophagy-related genes may be drug targets and have potential value in cancer prognosis and treatment. (A). Some autophagy-related genes are potential drug targets that are mainly involved in apoptosis regulation and PI3K/MTOR signaling pathways. The relationships among drugs, genes, and pathways were calculated with the oncoPredict R package [40] based on Genomics of Drug Sensitivity in Cancer (GDSC) data [41]. (B). Some autophagy-related genes indicate diverse expression distributions across different cancers according to sequencing data in The Cancer Genome Atlas (TCGA). * indicates significantly upregulated or downregulated in specific cancer (|log2FC| > 1.2 and padj < 0.05), using the limma package [42]. Abbreviations of cancers in (B): BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, Kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; STAD, stomach adenocarcinoma; THCA, thyroid carcinoma; UCEC, uterine corpus endometrial carcinoma. (C). Examples of the detailed expression distributions of autophagy-related genes across different cancers. For significantly upregulated or downregulated expression, log2FC and padj are also presented (red shows upregulated expression; blue shows downregulated expression). (D). Survival analysis (according to the starBase database [43]) shows that some genes may be associated with cancer prognoses.
Figure 2. Autophagy-related genes may be drug targets and have potential value in cancer prognosis and treatment. (A). Some autophagy-related genes are potential drug targets that are mainly involved in apoptosis regulation and PI3K/MTOR signaling pathways. The relationships among drugs, genes, and pathways were calculated with the oncoPredict R package [40] based on Genomics of Drug Sensitivity in Cancer (GDSC) data [41]. (B). Some autophagy-related genes indicate diverse expression distributions across different cancers according to sequencing data in The Cancer Genome Atlas (TCGA). * indicates significantly upregulated or downregulated in specific cancer (|log2FC| > 1.2 and padj < 0.05), using the limma package [42]. Abbreviations of cancers in (B): BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, Kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; STAD, stomach adenocarcinoma; THCA, thyroid carcinoma; UCEC, uterine corpus endometrial carcinoma. (C). Examples of the detailed expression distributions of autophagy-related genes across different cancers. For significantly upregulated or downregulated expression, log2FC and padj are also presented (red shows upregulated expression; blue shows downregulated expression). (D). Survival analysis (according to the starBase database [43]) shows that some genes may be associated with cancer prognoses.
Ijms 25 01561 g002aIjms 25 01561 g002b
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Figure 3. An example of autophagy-related RNA interactions based on ceRNA regulatory networks. Some lncRNAs and circRNAs have been reported as miRNA sponges to perturb the expression levels of autophagy-related genes.
Figure 3. An example of autophagy-related RNA interactions based on ceRNA regulatory networks. Some lncRNAs and circRNAs have been reported as miRNA sponges to perturb the expression levels of autophagy-related genes.
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Table 1. Some related genes at different stages of autophagy.
Table 1. Some related genes at different stages of autophagy.
Autophagy StageNameComposition
InitiationEnergy depletionAMPK
mTOR complexmTORC1
mTORC2
Class III PI3K
complex		Vps34
Vps15
ULK complexesFIP200
ULK1
ULK2
ATG13
ATG101
Class II PI3K
complex		Beclin-1
Vesicle nucleationClass III PI3K
complex		Vps34
Vps15
Class II PI3K
complex		Beclin-1
Bcl-2 familyBcl-2
-ATG14
Vesicle elongationAtg12-Atg5-Atg16ATG7
ATG5
ATG12
ATG16
LC3LC3-I
LC3-II
ATG4B
Autophagosome formation (Vesicle fusion) STX17
-ATG10
LC3LC3-I
LC3-II
-Rab7
-Rab5
-Rab9
Maturation and degradation-p62
LC3LC3II
-Rab7
-Rab8B
-Rab24
LAMPLAMP1
LAMP2
LAMP3
Table 2. Some related miRNAs at different stages of autophagy.
Table 2. Some related miRNAs at different stages of autophagy.
Autophagy StagemiRNADisease/CancerTargetFunctionSignaling Pathway/Axis Ref.
initiationmiR-20a/20bbreast cancerRB1CC1/FIP200Overexpression of miR-20a and miR-20b attenuates autophagy-[44]
initiationmiR-106alung adenocarcinomaULK1miRNA-106a targeted ULK1 results in death of different NSCLC cellsmiR-106a-ULK1 [45]
initiationmiR-489 breast cancerULK1, LAPTM4BmiR-489 affects autophagy by targeting ULK1-[46]
initiationmiR-25breast cancerULK1miR-25 functions as a regulator of autophagy by targeting ULK1-[47]
initiationmiR-142-5pgastric cancerULK1miR-142-5p can regulate ULK1 expression-[48]
initiationmiR-26non-small cell lung cancerTGF-β1miR-26 reduces autophagy via targeting TGF-β1TGF-β1-JNK
initiationmiR-17-5pcellsULK1miR-17-5p inhibits ULK1 expression in cellular autophagy-[49]
initiationmiR-26bbreast cancerDRAM1miR-26b can suppress autophagy in breast cancer cellsTGF-β1-JNK[50]
initiationmiR-885-3psquamous cell carcinomaULK2miR-885-3p contributes to the regulation of squamous cell carcinoma cell autophagy-[51]
initiationmiR-133a-3pgastric cancerATG13, GABARAPL1miR-133a-3p expression inhibits autophagy to hinder gastric cancer metastasis via blocking GABARAPL1 and ATG13 expression-[52]
initiationmiR-20aC2C12 myoblastsULK1miR-20a inhibits the expression of ULK1, which leads to a reduction in autophagy induced by leucine deprivationPI3K-AKT- MTOR [53]
initiationmiR-100renal cell carcinoma mTORmiR-100 can inactivate mTOR and thus increase autophagy in renal cancer cells.mTOR[54]
vesicle nucleationmiR-30ahepatic fibrosisBeclin-1Overexpression of miR-30a inhibits Beclin1-mediated autophagy to prevent the occurrence of liver fibrosis-[55]
vesicle nucleationmiR-93glioblastomaBECN1, Beclin-1, ATG5, ATG4B, SQSTM1/p62miR-93 inhibits autophagy functions by targeting multiple autophagy regulatorsPI3K-AKT[56]
vesicle nucleationmiR-124-3pbreast cancerBeclin-1, LC3-ImiR-124-3p promotes the progression of breast cancer cells by enhancing the expression of Beclin-1-[57]
vesicle nucleationmiR-30acardiomyocyteBeclin-1Downregulation of miR-30a expression upregulates beclin-1 expression and enhances autophagy in cardiomyocytes-[58]
vesicle nucleationmiR-30amedulloblastomaBeclin-1, LC3BmiR-30a inhibits autophagy by downregulating the expression of Beclin-1and LC3B-[59]
vesicle nucleationmiR-30ecardiomyopathyBeclin-1, LC3-I, LC3-IImiR-30e can downregulate the expression of Beclin-1-[60]
vesicle nucleationmiR-30dcolon cancerBeclin-1Overexpression of miR-30d inhibits the proliferation of colon cancer cells-[61]
vesicle nucleationmiR-30drenal cell carcinomaMTDHmiR-30d targets MTDH and inhibits renal cancer cellsAKT/FOXO[62]
vesicle nucleationmiR-124-3pbreast cancerBeclin-1Decreased miR-124-3p expression prompts breast cancer cell progression-[57]
vesicle nucleationmiR-216bnon-small cell lung cancerBeclin-1miR-216b can inhibit cisplatin sensitivity of NSCLC through regulating apoptosis and autophagy via miR-216b/Beclin-1 pathwaymiR-216b/Beclin-1 axis[63]
vesicle nucleationmiR-17-5pnon-small cell lung cancerBeclin-1miR-17-5p facilitates the ability of cell proliferation, inhibits autophagy and apoptosis by modulating Beclin-1-[64]
vesicle nucleationmiR-143colorectal cancerBeclin-1miR-143 targets various cellular that are involved in the autophagy pathways pathogenesis of colorectal cancerPI3K/AKT/Wnt[65]
elongationmiR-23a fibroblastsAMBRA1miR-23a inhibits the autophagy of fibroblasts during UV-induced photoaging-[66]
elongationmiR-23a-5pacute myeloid
leukemia		TLR2Downregulation of miR-23a-5p in leukemic cells can lead to the upregulation of protective autophagy-[67]
elongationmiR-7lung cancer AMBRA1AMBRA1 is targeted by miR-7, leading to the promotion of lung cancer cell proliferationAKT[68]
elongationmiR-128aosteoarthritisATG12ATG12, induced by miR-128a, loss represses chondrocyte autophagy to aggravate OA progression-[69]
elongationmiR-23btraumatic brain injuryATG12miR-23b directly targets to the 3′UTR region of ATG12 to suppress the activation of neuronal autophagy-[70]
elongationmiR-214colorectal cancerATG12, LC3miR-214 inhibits autophagy and induction of apoptosis by targeting ATG12-[71]
autophagosome formationmiR-106bcolorectal cancerATG16L1miR-106b inhibits starvation-induced autophagy by inhibiting the expression of ATG16L1-[72]
autophagosome maturationmiR-138-5ppancreatic cancerSIRT1miR-138-5p specifically targets SIRT1, thereby inhibiting autophagy.-[73]
autophagosome maturationmiR-487b-5plung cancerLAMP2miR-487b-5p directly targets LAMP2 to affect the latter stage of autophagy flux in lung cancer-[74]
autophagosome maturationmiR-205prostate cancerRAB27A, LAMP3miR-205 inhibits autophagy in prostate cancer cells-[75]
autophagosome maturationmiR-378-PDK1miR-378 promotes autophagy initiation through the mammalian target of rapamycin mTOR/ULK1 pathway and sustains autophagy by targeting phosphoinositide-dependent protein kinase 1 (PDK1)mTOR/ULK1[76]
Table 3. Some related lncRNAs at different stages of autophagy.
Table 3. Some related lncRNAs at different stages of autophagy.
Autophagy StagelncRNACancer/DiseaseTargetFunctionSignaling Pathways/AxisRefs.
initiationlncRNA NBR2 colorectal cancerAMPKAMPK promotes the activation of autophagy by binding to lncRNA NBR2mTOR[77]
initiationlncRNA AD5-A lncRNAhepatocellular carcinoma (HCC)AKT, mTOR Overexpression of AD5-A lncRNA can block the function of miRNAs to inhibit AKT/mTOR activity and promote autophagy activationAKT/mTOR[78]
initiationlncRNA SNHG6colorectal cancerULK1lncRNA SNHG6 is able to promote colorectal cancer chemoresistance and enhance autophagy through regulation of ULK1-[79]
initiationlncRNA MALAT1brain microvascular endothelial cell injuryULK2lncRNA MALAT1 can promote the expression of ULK2, suggesting that MALAT1 protects brain microvascular endothelial cells from ischemia-reperfusion injury by promoting autophagy-[80]
initiationlncRNA H19cardiomyocytesDIRAS3H19 could inhibit cardiomyocyte autophagy by epigenetically silencing DIRAS3mTOR[81]
initiationlncRNA SNHG1parkinson’s diseaseLC3-IIDownregulated lncRNA SNHG1 inhibits the mTOR pathway and initiates autophagymTOR[82]
initiationlncRNA AK156230mouse embryonic fibroblastsmTORAK156230 can inhibit replicative senescence (RS); meanwhile, the mTOR signaling pathway leads to autophagy deficiency, which may accelerate agingmTOR[83]
initiationlncRNA PTENP1hepatocellular carcinoma cellsAKTOverexpression of lncRNA PTENP1 indirectly inhibits the PI3K/AKT pathway and then induces pro-death autophagy, leading to the death of hepatocellular carcinoma cellsPI3K/AKT[84,85]
vesicle nucleationlncRNA SNHG12SH-SY5Y cellsLC3-II, Beclin-1The expression of lncRNA SNHG12 promotes LC3-II and Beclin-1 expression levels, thus inducing autophagy activation-[86]
vesicle nucleationlncRNA AC023115.3human glioblastoma cellsBeclin-1AC023115.3 is induced by cisplatin, and elevated AC023115.3 promotes cisplatin-induced apoptosis by inhibiting autophagymiR-26a-GSK3β-Mcl1 axis[87]
vesicle nucleationlncRNA PVT1-ATG14PVT1 interacts with ATG14 in the cytoplasm, and PVT1 can upregulate the expression of both Pygo2 and ATG14, thus regulating autophagic activity-[88]
vesicle nucleationlncRNA EIF3J-DTgastric cancerATG14EIF3J-DT activates autophagy and induces drug resistance in gastric cancer cells by targeting ATG14, thus contributing to activation of autophagy-[89]
vesicle nucleationlncRNA NEAT1Parkinson’s diseaseLC3-IIlncRNA NEAT1 can induce abnormal autophagy by stabilizing PINK1, which is an LC3-II upstream regulatory factor and plays a role in the pathogenesis of PD-[90]
elongationlncRNA CCAT1hepatocellular carcinoma cellATG7lncRNA CCAT1 facilitates hepatocellular carcinoma cell autophagy and cell proliferation, and then regulates ATG7 expression-[91]
elongationlncRNA GAS5osteoarthritisBeclin-1, ATG3, ATG5, ATG7, ATG12lncRNA GAS5, upregulating in osteoarthritis (OA), contributes to the pathogenesis of OA and thereby represses autophagy-[92]
elongationlncRNA HNF1A-AS1hepatocellular carcinomaATG5, Beclin-1, ATG12lncRNA HNF1A-AS1, binding to its target Beclin-1, ATG5, and ATG12, can provoke autophagy in hepatocellular carcinoma-[93]
elongationlncRNA HOTAIRhepatocellular carcinomaATG3, ATG7lncRNA HOTAIR is upregulated to promote hepatocellular carcinoma cell proliferation, probably by enhancing ATG3 and ATG7 expression-[94]
elongationlncRNA HULCepithelial ovarian carcinomaATG7, LC3-II, LAMP1lncRNA HULC overexpression reduces ATG7, LC3-II, and LAMP1 expression, and then reduces apoptosis and inhibits autophagy-[95]
Table 4. Some related circRNAs at different stages of autophagy.
Table 4. Some related circRNAs at different stages of autophagy.
Autophagy StagecircRNACancer/DiseaseTargetFunctionSignaling Pathway/AxisRef.
initiationcirc_0009910chronic myeloid leukemiaULK1circ_0009910 can regulate the expression of ULK1, thereby activating the level of autophagy-[96]
initiationcirc_CDYLbreast cancerATG7, ULK1circ_CDYL regulates the expression of autophagy-related genes ATG7 and ULK1, thus promoting autophagy-[97]
initiationcirc_PAN3acute myeloid leukemiamTORcirc-PAN3 regulates autophagy via the AMPK/mTOR signaling pathway in acute myeloid leukemiaAMPK/mTOR[98]
initiationcircRNA ACRRSC96 cellsmTORcircRNA ACR in RSC96 cells promotes the activation of the PI3K/AKT/mTOR pathway to alleviate autophagyPI3K/AKT/mTOR[99]
initiationcircRNA ciRS-7esophageal squamous cell carcinomamTORcircRNA ciRS-7 affects the AKT–mTOR signaling pathway, thus inhibiting autophagy of ESCC cellsAKT-mTOR[100]
vesicle nucleationcirc_MUC16epithelial ovarian cancerBeclin1, RUNX1, ATG13circ_MUC16 promotes autophagy in epithelial ovarian cancer by regulating Beclin1, RUNX1, and ATG13-[101]
vesicle nucleationcircPOFUT1gastric cancerATG12circPOFUT1 promotes ATG12 expression to regulate autophagy-associated chemoresistance in gastric cancer-[102]
elongationcirc_0092276breast cancerATG7, LC3-II, LC3-I, Beclin-1circ_0092276 affects autophagy and proliferation, and represses apoptosis of breast cancer cells-[103]
elongationcirc_0035483renal clear cell carcinoma cellsLC3-II, LC3-Iwhen circ_0035483 expression is downregulated, the LC3II/LC3I ratio is significantly reduced, thus inhibiting autophagy-[104]
Autophagosome formationcirc_ PABPN1intestinal epithelial cellsATG16L1circ_ PABPN1 inhibits ATG16L1 translation and thus regulates autophagy in intestinal epithelial cells-[105]
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Yang, X.; Xiong, S.; Zhao, X.; Jin, J.; Yang, X.; Du, Y.; Zhao, L.; He, Z.; Gong, C.; Guo, L.; et al. Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer. Int. J. Mol. Sci. 2024, 25, 1561. https://doi.org/10.3390/ijms25031561

AMA Style

Yang X, Xiong S, Zhao X, Jin J, Yang X, Du Y, Zhao L, He Z, Gong C, Guo L, et al. Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer. International Journal of Molecular Sciences. 2024; 25(3):1561. https://doi.org/10.3390/ijms25031561

Chicago/Turabian Style

Yang, Xueni, Shizheng Xiong, Xinmiao Zhao, Jiaming Jin, Xinbing Yang, Yajing Du, Linjie Zhao, Zhiheng He, Chengjun Gong, Li Guo, and et al. 2024. "Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer" International Journal of Molecular Sciences 25, no. 3: 1561. https://doi.org/10.3390/ijms25031561

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