The emerging co-regulatory role of long noncoding RNAs in epithelial-mesenchymal transition and the Warburg effect in aggressive tumors
Introduction
In the last several decades, cancer researchers have reported many distinct hallmarks of tumor cells (Hanahan and Weinberg, 2011). Among the mechanisms that lead to these phenotypes, epithelial-to-mesenchymal transition (EMT) is emerging as a central driver of several malignant behaviors (Kalluri and Weinberg, 2009). EMT is well defined as a series of events in which epithelial cells lose their epithelial characteristics, intercellular contacts and cellular polarity, and acquire various features of mesenchymal cells, such as increased motility, invasiveness, and resistance to apoptosis (Thiery et al., 2009). Accumulating evidence indicates that EMT-related processes endow carcinoma cells with cancer stem cell (CSC)-like properties, function as the initiation step of tumor metastasis, and are responsible for chemoresistance (Fischer et al., 2015; Wellner et al., 2009; Zheng et al., 2015).
At the molecular level, EMT is induced by a network of transcription factors (EMT-TFs), notably Snail, Slug, ZEB1, ZEB2, and Twist, that directly or indirectly represses the key epithelial marker E-cadherin (Lamouille et al., 2014). Signaling cascades contribute to the great complexity of EMT regulation (Thiery and Sleeman, 2006). Recent studies have shown that non-coding RNAs are also potent regulators of EMT, affecting the expression of multiple targets in the cascade and rendering carcinoma cells far more responsive to EMT-inducing signals (Heery et al., 2017; Xu et al., 2016).
Undergoing EMT is not a simple epithelial cancer cell behavior; an extremely complex network is required to orchestrate this process, and metabolic support and microenvironment modulation are the most indispensable (Li and Li, 2015; Sciacovelli and Frezza, 2017). Some researchers have reported that aggressive cancer cells can rewire their metabolism to gain adequate energy and nutrients, as well as fine tune the surrounding environmental conditions to facilitate their differentiated state (Huang and Zong, 2017; Schieber and Chandel, 2013; Zhao et al., 2017a).
Metabolic reprogramming is an enabling feature of cancer. A growing body of evidence suggests that normal cells and cancer cells exhibit different metabolic phenotypes. Almost all pyruvate from the glycolysis pathway flows into the tricarboxylic acid (TCA) cycle and is completely oxidized through oxidative phosphorylation (OXPHOS) under normoxia (Saraste, 1999). Anaerobic glycolysis will take place under hypoxic circumstances. Despite adequate oxygen, cancer cells tend to generate energy through glycolysis, rather than depending on OXPHOS, which is known as the Warburg effect or aerobic glycolysis (Martinez-Outschoorn et al., 2017; Vander et al., 2009).
In addition to ATP, proliferating cancer cells require nucleic acids, fatty acids, proteins, and membrane phospholipids to undergo rapid division. Glycolysis generates small molecule precursors or intermediates such as acetyl-CoA, non-essential amino acids, and ribose, which support the synthesis of biological macromolecules (Porporato et al., 2016). Aerobic glycolysis can also minimize reactive oxygen species (ROS) production in mitochondria and promote a more acidic extracellular pH via lactic acid release, establishing an appropriate microenvironment for tumor growth, invasion, and metastasis (Payen et al., 2016).
In general, reprogrammed cancer metabolism may help carcinoma cells adapt to environmental stressors, support the irregular molecular demand of rapid proliferation, and provide a basic fuel source for malignant biological processes. Current evidence indicates that EMT and metabolism work synergistically to promote tumor progression. It is plausible that the two biological processes share overlapping regulatory networks, but the mechanisms underlying both biological phenomena remain incompletely understood.
The Human Genome Project revealed that although more than 3 billion base pairs of the human genome are transcribed, less than 2% of them encode proteins. The vast majority of transcripts are not translated into proteins, and these are referred to as noncoding RNAs (ncRNAs) (Rinn and Chang, 2012). They are broadly divided into two categories according to their size: small ncRNAs less than 200 nucleotides and long non-coding RNAs (lncRNAs) over 200 nucleotides. The longer versions regulate gene expression at transcriptional or post-transcriptional levels, and they are involved in epigenetic modifications (Kung et al., 2013; Lee, 2012; Nagano and Fraser, 2011). Increasing evidence indicates that lncRNAs can function as oncogenes (e.g., HOTAIR, MALAT1/NEAT, H19, PVT1) or tumor suppressor genes (e.g., MEG3, GAS5, LincRNA-p21, PTENP1) (Beermann et al., 2016; Jiang et al., 2016). New findings suggest that lncRNAs play complex and precise regulatory roles in physiological and pathological processes (Fatica and Bozzoni, 2014). Dysregulation of lncRNAs could contribute to acquisition of malignant phenotypes including sustained proliferation, invasiveness, metastasis, angiogenesis, resistance to apoptosis, and reprogrammed energy metabolism; this would make them possible diagnostic or prognostic biomarkers and therapeutic targets for cancer (Batista and Chang, 2013; Ponting et al., 2009).
Section snippets
The reciprocal link between EMT and glycolysis
Since both aerobic glycolysis and EMT are closely associated with malignant cancer behaviors, a growing number of researchers have explored the link between the two processes. Elevated enzyme expression and activity associated with the Warburg effect provide cancer cells sufficient energy and metabolites for rapid biosynthesis, and the malignant phenotype of increased motility, invasion, and metastasis is concomitantly induced.
Several papers have described a series of glycolytic transporters
LncRNAs involved in both EMT and glycolysis
The lncRNAs which have been reported functionally involved in both EMT and glycolysis are summarized in Table1.
Conclusion and perspective
As discussed above, crosstalk between EMT and metabolic reprogramming synergistically contributes to cancer’s malignant behaviors. EMT plays a critical role in increasing tumor cell motility and invasiveness and is responsible for chemoresistance. Currently, EMT is detected based on examining molecular biomarkers in tumor cells or tissues. A non-invasive and effective imaging method to visualize EMT phenomena in clinical settings is still urgently needed as it could help predict early
Conflict of interest
Professor Huang has revised this review critically and final approved of the version to be submitted. Doctor Hua has designed the study and drafted the article. Doctor Mi has provided professional editing to this review. Each author certifies that he has not and will not receive payments or benefits from any commercial entity related to this work. They declare on conflict of interest. This manuscript has not been published in whole or in part nor is it being considered for publication
References (172)
- et al.
Attenuation of LDHA expression in cancer cells leads to redox-dependent alterations in cytoskeletal structure and cell migration
Cancer Lett.
(2013) - et al.
Long noncoding RNAs: cellular address codes in development and disease
Cell
(2013) - et al.
LincRNA-p21 impacts prognosis in resected non-small cell lung cancer patients through angiogenesis regulation
J. Thorac. Oncol.
(2016) - et al.
The over expression of long non-coding RNA AnRIL promotes epithelial-mesenchymal transition by activating the ATM-E2F1 signaling pathway in pancreatic cancer: an in vivo and in vitro study
Int. J. Biol. Macromol.
(2017) - et al.
MALAT1 induced migration and invasion of human breast cancer cells by competitively binding miR-1 with cdc42
Biochem. Biophys. Res. Commun.
(2016) - et al.
Long non-coding RNA PVT1 and cancer
Biochem. Biophys. Res. Commun.
(2016) - et al.
Loss of FBP1 by snail-mediated repression provides metabolic advantages in basal-like breast cancer
Cancer Cell
(2013) - et al.
CRNDE, a long non-coding RNA responsive to insulin/IGF signaling, regulates genes involved in central metabolism
Biochim. Biophys. Acta
(2014) - et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
Aberrant cancer metabolism in epithelial-mesenchymal transition and cancer metastasis: mechanisms in cancer progression
Crit. Rev. Oncol. Hematol.
(2017)
ALDOA functions as an oncogene in the highly metastatic pancreatic cancer
Cancer Lett.
Cadherin 11, a miR-675 target, induces N-cadherin expression and epithelial-mesenchymal transition in melasma
J. Invest. Dermatol.
Regulation of aerobic glycolysis by long non-coding RNAs in cancer
Biochem. Biophys. Res. Commun.
Epithelial-mesenchymal transition in human cancer: comprehensive reprogramming of metabolism, epigenetics, and differentiation
Pharmacol. Ther.
LncRNA, CRNDE promotes osteosarcoma cell proliferation, invasion and migration by regulating Notch1 signaling and epithelial-mesenchymal transition
Exp. Mol. Pathol.
Epithelial-mesenchymal transition and cancer stem cells, mediated by a long non-coding RNA, HOTAIR, are involved in cell malignant transformation induced by cigarette smoke extract
Toxicol. Appl. Pharmacol.
Posttranscriptional silencing of the lncRNA MALAT1 by miR-217 inhibits the epithelial-mesenchymal transition via enhancer of zeste homolog 2 in the malignant transformation of HBE cells induced by cigarette smoke extract
Toxicol. Appl. Pharmacol.
EZH2 promotes invasion and metastasis of laryngeal squamous cells carcinoma via epithelial-mesenchymal transition through H3K27me3
Biochem. Biophys. Res. Commun.
The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells
Biochim. Biophys. Acta
lncRNA H19 regulates epithelial-mesenchymal transition and metastasis of bladder cancer by miR-29b-3p as competing endogenous RNA
Biochim. Biophys. Acta
Long non-coding RNA TUG1 promotes cell proliferation and metastasis by negatively regulating miR-300 in gallbladder carcinoma
Biomed. Pharmacother.
No-nonsense functions for long noncoding RNAs
Cell
Novel concepts in insulin regulation of hepatic gluconeogenesis
Am. J. Physiol. Endocrinol. Metab.
The snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition
Oncogene
Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches
Physiol. Rev.
Expression of the Long non-coding RNA HOTAIR correlates with disease progression in bladder cancer and Is contained in bladder cancer patient urinary exosomes
PLoS One
The imprinted H19 noncoding RNA is a primary microRNA precursor
RNA
Regulation of cancer cell metabolism
Nat. Rev. Cancer
Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells
Carcinogenesis
Repression of E-cadherin by the polycomb group protein EZH2 in cancer
Oncogene
TUG1 promotes osteosarcoma tumorigenesis by upregulating EZH2 expression via miR-144-3p
Int. J. Oncol.
miR‑485‑5p inhibits bladder cancer metastasis by targeting HMGA2
Int. J. Mol. Med.
LncRNA CRNDE promotes hepatic carcinoma cell proliferation, migration and invasion by suppressing miR-384
Am. J. Cancer Res.
Down regulation of lincRNA-p21 contributes to gastric cancer development through Hippo-independent activation of YAP
Oncotarget
PVT1: a rising star among oncogenic long noncoding RNAs
Biomed. Res. Int.
ANRIL: molecular mechanisms and implications in human health
Int. J. Mol. Sci.
Decreasing lncRNA HOTAIR expression inhibits human colorectal cancer stem cells
Am. J. Transl. Res.
PKM2 regulates hepatocellular carcinoma cell epithelial-mesenchymal transition and migration upon EGFR activation
Asian Pac. J. Cancer Prev.
TGF-β-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12
Clin. Cancer Res.
Long non-coding RNAs: new players in cell differentiation and development
Nat. Rev. Genet.
Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance
Nature
Most mammalian mRNAs are conserved targets of microRNAs
Genome Res.
ROR functions as a ceRNA to regulate Nanog expression by sponging miR-145 and predicts poor prognosis in pancreatic cancer
Oncotarget
RNA sequencing of db/db mice liver identifies lncRNA H19 as a key regulator of gluconeogenesis and hepatic glucose output
Sci. Rep.
Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes
Cell Death Dis.
Long Non-Coding RNAs: key regulators of epithelial-mesenchymal transition, tumour drug resistance and cancer stem cells
Cancers (Basel)
miR-675 mediates downregulation of Twist1 and Rb in AFP-secreting hepatocellular carcinoma
Ann. Surg. Oncol.
Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor
Mol. Cell. Biol.
LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis
Cell Death Dis.
Upregulation of long noncoding RNA TUG1 promotes cervical cancer cell proliferation and migration
Cancer Med.
Cited by (17)
Biophysical signal transduction in cancer cells: Understanding its role in cancer pathogenesis and treatment
2020, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Some evidence indicates that the Warburg effect improves the stability of reactive oxygen species (ROS) in cancer cells by reducing their antioxidant capacity [55]. A study has also found that the Warburg effect and EMT are jointly regulated by long noncoding RNA (lncRNA) [56]. Although Carla Luisa et al. suggested that the metabolic mechanism of cancer cells may include the “Warburg effect inversion” in addition to the “Warburg effect” and demonstrated that the existence of the “Warburg effect inversion” under obesity conditions is more conducive to tumor diffusion [57], it is still undeniable that the products and metabolic processes of aerobic glycolysis increase the entropy and chaos in the internal environment.
The role of epithelial-mesenchymal transition in regulating radioresistance
2020, Critical Reviews in Oncology/HematologyCitation Excerpt :In addition, Warburg effect contributes to the promotion of radioresistance in aggressive cancers [116–118]. Current evidence suggests that EMT and metabolism promote tumor progression synergistically [115]. It is plausible that these lincRNAs may regulate radioresistance by crosstalk between EMT and Warburg effect-dependent metabolism in cancers.
Oncogenicity of lncRNA FOXD2-AS1 and its molecular mechanisms in human cancers
2019, Pathology Research and PracticeCitation Excerpt :Dysregulation of LncRNAs generally contributes to tumor-pertinent cellular processes such as cell promotion, proliferation, invasion and metastasis by controlling gene expression in multiple levels including working as miRNA sponges, protein scaffolds, regulatory signals or transcript decoys [25,26]. Related to clinical practice, lncRNAs are emerging as new biomarkers and therapeutic targets for cancer diagnosis/prognostication due to high tissue specificity and elevated efficiency [27–29]. Long noncoding RNA FOXD2 adjacent opposite strand RNA1 (lncRNA FOXD2-AS1), which is a 2527-bp lncRNA located on chromosome 1p33, is a promising candidate among all tumor-related lncRNAs.
Long non-coding RNA SNHG7 silencing confers protection against epithelial-mesenchymal transition in ovarian cancer cells via microRNA-34a-targeted EDG4 and the PI3K/AKT pathway
2021, Journal of Biological Regulators and Homeostatic Agents
- 1
These authors contributed equally to this review and should be considered co-first authors.