The emerging co-regulatory role of long noncoding RNAs in epithelial-mesenchymal transition and the Warburg effect in aggressive tumors

https://doi.org/10.1016/j.critrevonc.2018.03.028Get rights and content

Highlights

  • Systematically summaprized the reported lncRNAs that have co-regulatory roles in epithelial-mesenchymal transition and the Warburg effect.

  • Explored the detailed mechanisms of lncRNAs in both biological process that could help elucidate the co-regulatory network.

  • Provide a theoretical basis for clinical management of EMT-related malignant phenotypes from metabolic perspective, such as the application of FDG-PET.

Abstract

Malignant tumor cells have several unique characteristics, and their ability to undergo epithelial–mesenchymal transition (EMT) is a molecular gateway to invasive behavior. Rapid proliferation and increased invasiveness during EMT enhance aberrant glucose metabolism in tumor cells. Meanwhile, aerobic glycolysis provides energy, biosynthesis precursors, and an appropriate microenvironment to facilitate EMT. Reciprocal crosstalk between the processes synergistically contributes to malignant cancer behaviors, but the regulatory mechanisms underlying this interaction remain unclear. Long non-coding RNAs (lncRNAs) are a recently recognized class of RNAs involved in multiple physiological and pathological tumor activities. Increasing evidence indicates that lncRNAs play overlapping roles in both EMT and cancer metabolism. In this review, we describe the lncRNAs reportedly involved in the two biological processes and explore the detailed mechanisms that could help elucidate this co-regulatory network and provide a theoretical basis for clinical management of EMT-related malignant phenotypes.

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)

  • S. Ji et al.

    ALDOA functions as an oncogene in the highly metastatic pancreatic cancer

    Cancer Lett.

    (2016)
  • N.H. Kim et al.

    Cadherin 11, a miR-675 target, induces N-cadherin expression and epithelial-mesenchymal transition in melasma

    J. Invest. Dermatol.

    (2014)
  • X.Z. Kong et al.

    Regulation of aerobic glycolysis by long non-coding RNAs in cancer

    Biochem. Biophys. Res. Commun.

    (2016)
  • L. Li et al.

    Epithelial-mesenchymal transition in human cancer: comprehensive reprogramming of metabolism, epigenetics, and differentiation

    Pharmacol. Ther.

    (2015)
  • Z. Li et al.

    LncRNA, CRNDE promotes osteosarcoma cell proliferation, invasion and migration by regulating Notch1 signaling and epithelial-mesenchymal transition

    Exp. Mol. Pathol.

    (2018)
  • Y. Liu et al.

    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.

    (2015)
  • L. Lu et al.

    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.

    (2015)
  • H. Luo et al.

    EZH2 promotes invasion and metastasis of laryngeal squamous cells carcinoma via epithelial-mesenchymal transition through H3K27me3

    Biochem. Biophys. Res. Commun.

    (2016)
  • F. Luo et al.

    The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

    Biochim. Biophys. Acta

    (2016)
  • M. Lv et al.

    lncRNA H19 regulates epithelial-mesenchymal transition and metastasis of bladder cancer by miR-29b-3p as competing endogenous RNA

    Biochim. Biophys. Acta

    (2017)
  • F. Ma et al.

    Long non-coding RNA TUG1 promotes cell proliferation and metastasis by negatively regulating miR-300 in gallbladder carcinoma

    Biomed. Pharmacother.

    (2017)
  • T. Nagano et al.

    No-nonsense functions for long noncoding RNAs

    Cell

    (2011)
  • A. Barthel et al.

    Novel concepts in insulin regulation of hepatic gluconeogenesis

    Am. J. Physiol. Endocrinol. Metab.

    (2003)
  • C. Battistelli et al.

    The snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition

    Oncogene

    (2017)
  • J. Beermann et al.

    Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches

    Physiol. Rev.

    (2016)
  • C. Berrondo et al.

    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

    (2016)
  • X. Cai et al.

    The imprinted H19 noncoding RNA is a primary microRNA precursor

    RNA

    (2007)
  • R.A. Cairns et al.

    Regulation of cancer cell metabolism

    Nat. Rev. Cancer

    (2011)
  • S. Cannito et al.

    Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells

    Carcinogenesis

    (2008)
  • Q. Cao et al.

    Repression of E-cadherin by the polycomb group protein EZH2 in cancer

    Oncogene

    (2008)
  • J. Cao et al.

    TUG1 promotes osteosarcoma tumorigenesis by upregulating EZH2 expression via miR-144-3p

    Int. J. Oncol.

    (2017)
  • Z. Chen et al.

    miR‑485‑5p inhibits bladder cancer metastasis by targeting HMGA2

    Int. J. Mol. Med.

    (2015)
  • Z. Chen et al.

    LncRNA CRNDE promotes hepatic carcinoma cell proliferation, migration and invasion by suppressing miR-384

    Am. J. Cancer Res.

    (2016)
  • Y. Chen et al.

    Down regulation of lincRNA-p21 contributes to gastric cancer development through Hippo-independent activation of YAP

    Oncotarget

    (2017)
  • T. Colombo et al.

    PVT1: a rising star among oncogenic long noncoding RNAs

    Biomed. Res. Int.

    (2015)
  • A. Congrains et al.

    ANRIL: molecular mechanisms and implications in human health

    Int. J. Mol. Sci.

    (2013)
  • J. Dou et al.

    Decreasing lncRNA HOTAIR expression inhibits human colorectal cancer stem cells

    Am. J. Transl. Res.

    (2016)
  • F.T. Fan et al.

    PKM2 regulates hepatocellular carcinoma cell epithelial-mesenchymal transition and migration upon EGFR activation

    Asian Pac. J. Cancer Prev.

    (2014)
  • Y. Fan et al.

    TGF-β-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12

    Clin. Cancer Res.

    (2014)
  • A. Fatica et al.

    Long non-coding RNAs: new players in cell differentiation and development

    Nat. Rev. Genet.

    (2014)
  • K.R. Fischer et al.

    Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance

    Nature

    (2015)
  • R.C. Friedman et al.

    Most mammalian mRNAs are conserved targets of microRNAs

    Genome Res.

    (2009)
  • S. Gao et al.

    ROR functions as a ceRNA to regulate Nanog expression by sponging miR-145 and predicts poor prognosis in pancreatic cancer

    Oncotarget

    (2016)
  • N. Goyal et al.

    RNA sequencing of db/db mice liver identifies lncRNA H19 as a key regulator of gluconeogenesis and hepatic glucose output

    Sci. Rep.

    (2017)
  • J.R. Hall et al.

    Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes

    Cell Death Dis.

    (2015)
  • R. Heery et al.

    Long Non-Coding RNAs: key regulators of epithelial-mesenchymal transition, tumour drug resistance and cancer stem cells

    Cancers (Basel)

    (2017)
  • J.M. Hernandez et al.

    miR-675 mediates downregulation of Twist1 and Rb in AFP-secreting hepatocellular carcinoma

    Ann. Surg. Oncol.

    (2013)
  • N. Herranz et al.

    Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor

    Mol. Cell. Biol.

    (2008)
  • P. Hou et al.

    LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis

    Cell Death Dis.

    (2014)
  • Y. Hu et al.

    Upregulation of long noncoding RNA TUG1 promotes cervical cancer cell proliferation and migration

    Cancer Med.

    (2017)
  • Cited by (17)

    • Biophysical signal transduction in cancer cells: Understanding its role in cancer pathogenesis and treatment

      2020, Biochimica et Biophysica Acta - Reviews on Cancer
      Citation 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/Hematology
      Citation 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 Practice
      Citation 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.

    View all citing articles on Scopus
    1

    These authors contributed equally to this review and should be considered co-first authors.

    View full text