The landscape of long non-coding RNAs in tumor stroma

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Review article

The landscape of long non-coding RNAs in tumor stroma Md. Nazim Uddin a, b, c, d, Xiaosheng Wang a, b, c, * a

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China c Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China d Institute of Food Science and Technology, Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka 1205, Bangladesh b

A R T I C L E I N F O

A B S T R A C T

Keywords: Long non-coding RNAs Tumor-stroma crosstalk Tumor stroma Tumor microenvironment Cancer therapy

Aims: Long non-coding RNAs (lncRNAs) are associated with cancer development, while their relationship with the cancer-associated stromal components remains poorly understood. In this review, we performed a broad description of the functional landscape of stroma-associated lncRNAs in various cancers and their roles in regulating the tumor-stroma crosstalk. Materials and methods: We carried out a systematic literature review of PubMed, Scopus, Medline, Bentham, and EMBASE (Elsevier) databases by using the keywords “LncRNAs in cancer,” “LncRNAs in tumor stroma,” “stroma,” “cancer-associated stroma,” “stroma in the tumor microenvironment,” “tumor-stroma crosstalk,” “drug resistance of stroma,” and “stroma in immunosuppression” till July 2020. We collected the latest articles addressing the biological functions of stroma-associated lncRNAs in cancer. Key findings: These articles reported that dysregulated stroma-associated lncRNAs play significant roles in modulating the tumor microenvironment (TME) by the regulation of tumor-stroma crosstalk, epithelial to mesenchymal transition (EMT), endothelial to mesenchymal transition (EndMT), extracellular matrix (ECM) turnover, and tumor immunity. Significance: The tumor stroma is a substantial portion of the TME, and the dysregulation of tumor stromaassociated lncRNAs significantly contributes to cancer initiation, progression, angiogenesis, immune evasion, metastasis, and drug resistance. Thus, stroma-associated lncRNAs could be potentially useful targets for cancer therapy.

1. Introduction In the nucleus of human cells, approximately 90% of the genome sequence is properly transcribed into RNA, but less than 2% can be translated into functional proteins. The rest untranslated portion is regarded as “dark matter”, which contains a vast portion of functional non-coding RNAs (ncRNAs), as demonstrated by the ENCODE project [1–3]. Notably, long non-coding RNAs (lncRNAs) constitute a major part of ncRNAs [4], which are involved in the crucial biological processes in human physiology and diseases [5]. LncRNAs play important roles in regulating tumor-suppressive and oncogenic pathways [6]. Their aber­ rant expression has been associated with tumorigenesis [7–14]. Partic­ ularly, dysfunction of lncRNAs is associated with the hallmarks of cancer, including activating proliferative signaling pathways, evading growth factor suppression, enabling replicative immortality, promoting

immune invasion, activating metastasis, regulating angiogenesis, and inhibiting cell death [15]. Besides, dysregulated lncRNAs act as master regulators of cancer through regulating cellular signaling [16], drive cancer phenotypes via interacting with DNA, protein, RNA, and other macromolecules [17], and affect tumor cellular homeostasis, such as proliferation, migration, and genomic stability [18]. Numerous studies have identified therapeutically targetable lncRNAs that exhibit aberrant expression in cancerous states and regulate cancer-associated pathways at the replication, transcription, post-transcription, translation, posttranslation, or epigenetic level [19–24]. Cancers are complex ‘ecosystems’ composed of various types of cells in the compartment of the tumor microenvironment (TME) [25]. Functions of stromal cells are modified in the TME [26]. In the tumorstroma crosstalk, tumor cells meet with stromal and immune cells, thereby contributing to tumor progression [27]. Indeed, tumor pro­ gression is a process of interactions between epithelial and stromal cells

* Corresponding author at: Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China. E-mail address: [email protected] (X. Wang). https://doi.org/10.1016/j.lfs.2020.118725 Received 18 July 2020; Received in revised form 26 October 2020; Accepted 3 November 2020 Available online 6 November 2020 0024-3205/© 2020 Elsevier Inc. All rights reserved.

Please cite this article as: Md. Nazim Uddin, Xiaosheng Wang, Life Sciences, https://doi.org/10.1016/j.lfs.2020.118725

Md.N. Uddin and X. Wang

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Abbreviations

GBM HCC MM EC EPC HIF-1 NSCLC OS MMP ESCC EV CRC IL-33 RNCR3 GC

lncRNA long non-coding RNA TME tumor microenvironment ECM extracellular matrix EMT epithelial-to-mesenchymal transition EndMT endothelial-to-mesenchymal transition CAF cancer associated fibroblast MSC mesenchymal stem cell MDSC myeloid-derived suppressor cell TAM tumor associated macrophage TGF-β1 transforming growth factor-1 NOF normal fibroblast TF transcription factor HIF1A-AS2 hypoxia-inducible factor 1 alpha-antisense RNA 2

glioblastoma multiforme hepatocellular carcinoma multiple myeloma endothelial cell endothelial progenitor cell hypoxia inducible factor-1 non-small cell lung cancer osteosarcoma matrix metalloprotease esophageal squamous cell carcinoma extracellular vesicle colorectal cancer interleukin-33 retinal non-coding RNA3 gastric cancer

Fig. 1. The lncRNAs associated with tumor-stroma interactions in cancer. The tumor stroma-associated lncRNAs involved in interactions between solid tumor cells and tumor-associated stromal components are presented. lncRNA: long non-coding RNA; CAFs: cancer-associated fibroblasts; MSC: mesenchymal stem cell; EV: extracellular vesicle; ECM: extracellular matrix; MDSC: myeloid-derived suppressor cell; TAMs: tumor-associated macrophages (These also apply to the following figures).

[26]. Stromal and epithelial cellular interaction and reprogramming may induce malignant epithelium, remodel stroma, and confer aggres­ sive phenotype of stromal cells [28–30]. Stroma-associated gene signa­ tures have been linked with prognosis in multiple cancers. For example, breast cancer stroma gene signatures are indicative of unfavorable clinical outcomes [31,32]. In colon cancer stroma, transcriptional sig­ natures are associated with poor prognosis [33,34]. The ZEB1/p53 signaling pathway is stroma-specific, which in turn promotes mammary epithelial tumors [35]. LncRNAs participate in the tumor-stroma crosstalk [36] to contribute to angiogenesis, immune evasion, extracellular matrix (ECM) turnover, metastasis, and the response to TME-associated hypoxic stress [37–41]. Cancer-associated stromal (CAS) components participate in the communication network with tumor cells and transform the epithelium through a complex molecular network of extracellular signaling path­ ways. LncRNAs play important roles in regulating the phenotype of CAS cells in the TME and are associated with tumor-stroma signaling during

tumor initiation, adhesion, progression, and metastasis. Fig. 1 and Table 1 illustrate the stromal LncRNAs associated with oncogenic signaling and tumor-stroma interactions. In this review, we recapitulated the oncogenic and tumorsuppressive functions of lncRNAs in cancer-associated tumor stroma and their significance within the TME. We also discussed associations of lncRNAs with tumor-stroma crosstalk, epithelial to mesenchymal tran­ sition (EMT), endothelial to mesenchymal transition (EndMT), ECM turnover, metastasis, immunosuppression, and drug resistance. Furthermore, we displayed several tumor stroma-associated lncRNAs that regulate various TME-associated signaling pathways. 2. Association of lncRNAs with cancer-associated fibroblasts (CAFs) CAF is a substantial cellular part of stroma in the TME and plays crucial roles in promoting tumorigenesis and chemoresistance [42]. 2

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Table 1 A list of lncRNAs associated with the tumor-stroma crosstalk in solid tumors. LncRNA

Expression

Stroma component

Cancer type

ZEB2NAT

Up

CAF

Bladder

Pathway

Cellular function

Reference

EMT

[48]

Metastasis

[49]

Metastasis

[53]

Metastasis Metastasis

[53] [54]

DNA damage response

[55]

Autophagy-lysosome degradation

[57]

mTOR

Proliferation and metastasis

[59]

β-catenin

Tumor chemoresistance

[209]

S100A7/

Tumor progression

[220]

EMT markers

EMT

[60]

DHX9/

Adaptive response to hypoxic stress

[64]

EMT

[65]

TGFβ1 ZEB2NATZEB2

CASC9

Up

CAF

Cervical

FLJ39739, GAS5, H19, TUG1, MALAT1, NEAT1, LOC100499466

Up

CAF

Ovarian

miR-215/ TWIST2 Focal adhesion, ECM-receptor

CASC2, DLEU2, HCG18, LOC100133669 LINC00092

Down Up

CAF CAF

Ovarian Ovarian

DNM3OS

Up

CAF

ESCC

interaction Unknown Glycolysis PDGFβ / PDGFβR / FOXO1

LncRNA-CAF

Up

CAF

OSCC

UCA1

Up

CAF

CRC

CCAL

UP

CAF

CRC

TBILA

Up

CAF

NSCLC

LincK

Up

MSC

Breast

HIF1A-AS2

Up

MSC

GBM

MUF

Up

MSC

HCC

MEG3

Up

MSC

MM

BMP4 transcription

Osteogenic differentiation

[6]

H19

Up

MSC

Bone

Notch signaling

Osteogenic differentiation

[80]

H19

Up

EC

Glioma

miR-29a

[86]

MALAT-1

Up

EC

Neuroblastoma

FGF2 expression

Carcinogenesis, angiogenesis, and metastasis Tumor-driven angiogenesis

MCM3AP-AS1

UP

EC

Neuroblastoma

MCM3AP-AS1 /

Angiogenesis

[97]

LncRNA-CAF / interleukin-33

JAB1

IGF2BP-2 Wnt/ β-catenin

[104]

miR-211 / KLF5 / AGGF1 XIST

Up

EC

Glioma

MALAT1

Up

Osteoblasts

Prostate

miR-137 SOST/

BTB permeability and glioma angiogenesis

[101]

Metastasis

[135]

Osteosarcoma growth

[136]

Proliferation, migration, and invasion

[141]

Repress metastasis

[181]

Wnt/ MALAT1 lncRNA-ANCR

Down

Osteoblasts

OS

ASBEL

Down

Osteoblasts

OS

EZH2, p21 and p27 ASBELmiR-21 PP2A

H19

Up

ECM

Prostate

(continued on next page)

3

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Table 1 (continued ) LncRNA

Expression

Stroma component

Cancer type

Pathway

Cellular function

Reference

ICAM1 regulation

Metastasis

[183]

HOTAIR/

Tumor progression

[186]

Metastasis

[188]

Tumorigenesis

[189]

Invasion and metastasis

[190]

Immunosuppression

[161]

Immunosuppression

[168]

Inhibit immunosuppression

[171]

RUNX1

Immunosuppression

[172]

HOXA1

Tumor progression

[174]

Lnc-BM/

Breast cancer brain metastases

[237]

Proliferation, migration and invasion

[238]

Glycolysis, poor chemotherapeutic response, and shorter survival Proliferation, migration, invasion, and angiogenesis

[239]

H19/ miR-675 axis

lncRNA-ECM

Up

ECM

ESCC

HOTAIR

Up

ECM

Lung

Col-1/

α2β1 integrin SNHG5

Up

ECM

HCC

miR-26a-5p/ GSK3β and MMP-2 and MMP-9

DLX6-AS1

Up

ECM

HCC

DLX6-AS1/ miR-203a/ MMP-2

ZFAS1

Up

ECM

HCC

miR-150 / ZEB1 / MMP14/ MMP16

RNCR3

Up

MDSCs

Melanoma

RNCR3/ miR-185-5p/ Chop

Olfr29-ps1

Up

MDSCs

Melanoma

Olfr29-ps1/ miR-214-3p/ MyD88

Lnc-C/EBPβ

Up

MDSCs

Colon

RUNXOR

Up

MDSCs

Lung

HOTAIRM1

Up

MDSCs

Lung

Lnc-BM

Up

TAMs

BCBM

Interaction of LIP and LAP

JAK2/ STAT3 GNAS-AS1

Up

TAMs

ER+ breast

GNAS-AS1/ miR-433-3p/ GATA3

HISLA

Up

TAMs

Breast

HIF-1α

MALAT1

Up

TAMs

Thyroid

FGF2

[240]

Note: The “ ” indicates the upregulation, and the “ ” indicates the downregulation of regulated molecules.

CAFs originate from various types of stromal components or progenitor cells, including fibroblasts, adipocytes, smooth muscle cells, stellate cells, epithelial cancer cells, as well as migratory bone marrow-derived mesenchymal stem cells (MSCs) [43–45]. CAF is a heterogeneous type of tumor stromal cells and represents phenotypically similar cells in the TME [46]. CAFs render tumor cells susceptible to proliferation,

migration, and invasion through the aberrant expression and secretion of immunological mediators, including chemokines, cytokines, growth factors, prostaglandins, basal lamina or extracellular matrix molecules, and adhesion molecules and signaling receptors [44,47]. The transforming growth factor beta-1 (TGF-β1) is one of EMTassociated proteins in CAFs, whose secretion is regulated by lncRNA 4

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The downregulation of lncRNA MEG3 has been linked with cancer initiation, adhesion, migration, metastasis, and drug-resistance [69]. Numerous studies have reported the downregulation of MEG3 in various types of cancers [70,71], including prostate cancer [72], lung cancer [73], hepatocellular cancer [74], meningioma [75], gastric cancer [76], glioma [77], and multiple myeloma (MM) [78]. Impaired osteogenic differentiation of MSCs is a characteristic of MM. MSCs derived from MM have significantly lower expression levels of MEG3 during osteo­ genic differentiation. Another lncRNA H19 was involved in tumor initiation, progression, invasion, and metastasis in various cancers [79]. MSC-associated H19 is essential in the development of bone tumors [80]. H19 plays a potential role in controlling notch receptors and/or ligands-interacting miRNAs (such as miR-107, 27b, 106b, 125a, and 17) in response to BMP9 stimulation in MSCs [80]. In contrast, lncRNA DANCR overexpression inactivates the p38 MAPK pathway which ulti­ mately negatively regulating the proliferation and osteogenic differen­ tiation of human bone marrow MSCs [81].

ZEB2NAT [48]. TGF-β1 is a potential inducer of EMT-associated genes to promote the invasion of urinary bladder cancer cells [48]. CAFs-derived transforming growth factor β (TGF-β) can stimulate the overexpression of lncRNA CASC9 to control cervical cancer metastasis by meditating miR-215/TWIST2 signaling [49]. Mechanistically, dysregulation of CASC9 sponges miR-215 to increase the expression of TWIST2 by pre­ venting the binding of miR-215 with 3’UTR of TWIST2 [49]. MiR-215 functions as a tumor suppressor in epithelial ovarian cancer [50], colorectal cancer (CRC) [51], and non-small cell lung cancer (NSCLC) [52]. LncRNAs also have significant roles in ovarian cancer metastasis. A computational analysis [53] identified seven lncRNAs (GAS5, H19, FLJ39739, LOC100499466, MALAT1, NEAT1, and TUG1), which were upregulated in CAFs versus normal fibroblasts (NOFs) and were involved in multiple metastasis-associated pathways in ovarian cancer, including focal adhesion and the ECM receptor interaction. This study also detected co-regulatory modules containing downregulated lncRNAs (CASC2, DLEU2, HCG18, and LOC100133669) in CAFs. The down­ regulation of these lncRNAs was associated with the elevated enrich­ ment of cancer metastatic pathways. Another study [54] showed that CAFs released the chemokine CXCL14, which in turn induced LINC00092. This phenomenon alters the glycolysis in tumor cells through the binding of LINC00092 with fructose-2,6-biphosphatase (PFKFB2), a glycolytic enzyme. The altered glycolysis, coupling with the sustaining local supportive function of CAFs within the TME, pro­ motes the metastasis process [54]. In esophageal squamous cell carci­ noma, CAFs significantly increase the expression of lncRNA DNM3OS in a PDGFβ/PDGFβR/FOXO1 axis-dependent manner to confer significant radiotherapy resistance by regulating DNA damage response [55]. Teng et al. [56] found 766 lncRNAs abnormally expressed in CAFs versus NOFs. These lncRNAs were mainly associated with tumor immune regulation. Ding et al. [57] uncovered a novel stromal lncRNA signature FLJ22447/lncRNA-CAF(Lnc-CAF), which was remarkably upregulated in CAFs and whose expression was an adverse prognostic factor in oral squamous cell carcinoma. Walters et al. [58] identified 12 CAFsassociated lncRNAs by the pan-cancer analysis of 32 cancer types, among which lncAC093850.2 was correlated with the transformation of NOFs to a CAF phenotype. CAFs may influence proliferation and metastasis of CRC cells by inciting lncRNA UCA1 [59]. To summarize, these findings indicate that mediation of CAFs-derived oncogenic pathways through controlling CAF-associated lncRNAs could serve as a new treatment avenue for cancer patients.

4. Association of lncRNAs with endothelial cells (ECs) and tumor angiogenesis Vascular ECs reside in the compartment of stroma and function in regulating tumor intravasation through the angiogenic process, an essential prerequisite for tumor progression [82]. Tumor ECs interact with cancer cells through the juxtacrine and paracrine signaling in the TME during tumor intravasation and metastasis [83]. Recent studies have demonstrated the role of lncRNAs in regulating angiogenesis whereby to modulate tumor development and metastasis [84,85]. Many lncRNAs associated with tumor angiogenesis have been identified in ECs. For example, in microvessels originated from glioma tissue and glioma-associated ECs, H19 is upregulated, and H19 knockdown can inhibit glioma-induced proliferation, migration, and tube formation [86]. H19 stimulates the endothelial signaling by enhancing vasohibin-2 protein expression and regulates angiogenesis by repressing miR-29a expression in glioma [86]. MiR-29a, a tumor suppressor gene, can affect chemoresistance, tumor cell growth, migration, invasion, and apoptosis [87] and regulates several oncogenic genes, including KDM5B [88], CDC42 [89], CLDN1 [90], MYC [91], and TNFR1 [92]. H19 also regulates the EC proliferation, migration, and network formation in glioma, thereby promoting the initiation, invasion, angiogenesis, and stemness of glioblastoma cells [93–95]. LncRNA PVT1 is overexpressed in vascular ECs and promotes vascular EC proliferation, migration, and angiogenesis in glioma [96]. LncRNA MCM3AP-AS1 is overexpressed in glioma-associated ECs, whose knockdown results in the reduced expression of KLF5 and AGGF1 and the inactivation of crucial signaling pathways (PI3K/AKT and ERK1/2), thereby promoting glioma angio­ genesis [97]. In the hypoxic microenvironment, by repressing miR-186 expression, PVT1 upregulates the expression of autophagy genes ATG7 and BECN1 to promote vascular EC survival in glioma [98]. In glioma cells, lncRNA HOTAIR affects glioma angiogenesis through the control of VEGFA expression to transmit this genetic material into ECs [99]. In nasopha­ ryngeal carcinoma cells, HOTAIR stimulates angiogenesis via directly activating VEGFA and GRP78, which in turn enhances VEGFA and ANG2 expression [100]. LncRNA XIST is upregulated in glioma ECs and its knockdown increases the blood-tumor barrier permeability, thereby inhibiting the angiogenesis of glioma [101]. In mechanism, XIST upre­ gulation repressed miR-137 expression via promoting the activation of FOXC1 and ZO-2. FOXC1 overexpression increases the expression of ZO1 and occuludin and stimulates angiogenesis by increasing CXCR7 expression [101]. The aberrated expression of miR-137 can inhibit the proliferation and invasion of glioma cells through inversely regulating Cox-2 [102]. LncRNA OR3A4 is upregulated in gastric cancer cells to incite tubule formation in human umbilical vein ECs, thereby promoting tumor initiation, growth, progression, and metastasis [103]. OR3A4 can induce tumor angiogenesis by activating the expression of PDLIM2,

3. Association of lncRNAs with MSCs As a component of tumor stroma, MSCs play a significant role in the TME [60]. MSCs secrete cytokines, such as CCL5, IL-6, and TGF-β, to promote cancer progression [61–63]. A recent study [60] revealed the overexpression of lncRNA KB-1732A1.1 (LincK) in breast cancer compared to normal tissue. The overexpression of LincK could induce EMT via downregulating the epithelial marker CDH1/E-cadherin and ZO-1 and upregulating the mesenchymal marker CDH2/N-cadherin [60]. Consequently, LincK overexpression may promote the prolifera­ tion, invasion, progression, and metastasis of breast cancer cells [60]. Hypoxia-inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) is a MSC-specific lncRNA in glioblastoma multiforme (GBM), which is upregulated in mesenchymal GBM stem-like cells (GSCs) [64]. HIF1AAS2 regulates the growth, survival, and molecular programming of GSCs in a hypoxia-dependent manner, suggesting its adaptive response to hypoxic stress in the TME [64]. MSCs could stimulate the expression of lncRNA-MUF in hepatocellular carcinoma (HCC) and confer aggres­ sive mesenchymal phenotype in HCC [65]. The potential mechanism could be the activation of the Wnt/β-catenin pathway by lncRNA-MUF through its interaction with annexin A2 to induce EMT by inhibiting miR-34a expression [65]. MiR-34a acts as a tumor suppressor by repressing the expression of oncogenic molecules, including MYC, NOTCH1, MET, CDK4/6, BCL2, and CD44 [66–68]. 5

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Fig. 2. Tumor stroma-associated lncRNAs implicated in cancer metastasis. The pathways associated with the EndMT process, including TGF-β, ET-1, NOTCH, CAV-1, Wnt, SHH, and hypoxia. LncRNAs GATA6-AS and MALAT1 positively modulate the EndMT, a process by which endothelial cells are transformed into malignancies. LncRNA H19 negatively modulates the EndMT process. CAFs promote metastasis by secreting cytokines, such as TGF-β1, to induce EMT of cancer cells. LncRNAs ZEB2NAT, MUF, HOTAIR, and LincK can induce the EMT to promote cancer metastasis in the tumor microenvironment. EndMT: endothelial-tomesenchymal transition; EMT: the epithelial to mesen­ chymal transition (These also apply to the following figures).

MACC1, NTN4, and GNB2L1 [103]. In human neuroblastoma cells under the hypoxic condition, lncRNA MALAT1 stimulates tumor angiogenesis by upregulating the expression of pro-angiogenic genes [104]. LncRNA MEG3 can inhibit the proliferation and migration of EC cells [105]. As tumor suppressor, MEG3 is downregulated in various cancers, including breast cancer [106], endometrial carcinoma [94], cervical cancer [95], and testicular germ cell tumor [107].

angiogenesis, a crucial vascular mechanism for tumor initiation, growth, migration, and metastasis [126]. HIF-1 regulates the expression of numerous lncRNAs. For example, lncRNA UCA1 is one of the HIF-1 targets that fosters initiation, proliferation, invasion, progression, and metastasis in hypoxic bladder cancer [127]. In NSCLC, HIF-1 is bound to the promoter of HOTAIR to promote tumor cell proliferation, progres­ sion, and invasion in the hypoxic TME [128].

5. Association of lncRNAs with the endothelial-mesenchymal transition (EndMT) and tumor metastasis

6. Association of lncRNAs with osteoblasts Osteoblasts are a type of stromal cell responsible for bone and ECM formation [129]. Osteoblasts play crucial roles in cancer metastasis [130,131], maintenance of inflammation [132], osteolysis, and survival [133,134] in the bone microenvironment. LncRNAs of osteoblasts are associated with various cancers. For example, MALAT1 is upregulated in osteoblasts in prostate cancer [135]. LncRNA-ANCR is more highly expressed in osteosarcoma (OS) cells than in osteoblasts. It modulates the proliferation of OS cells through the interaction with EZH2 to in­ crease the expression of p21 and p27 at both transcriptional and trans­ lational levels [136]. Some other lncRNAs, including HOXA11-AS [137], HOTAIR [138], TP73-AS1 [139], MALAT1 [140], ASBEL [141], and MEG3 [142], are also upregulated in OS cells versus osteoblast. The overexpression of these lncRNAs is associated with the survival, differ­ entiation, migration, invasion, and metastasis of OS cells. In contrast, lncRNA WWOX-AS1 is downregulated in OS cells versus osteoblasts and plays a role in inhibiting the proliferation, progression, and invasion of OS cells [143]. Collectively, abundant evidence has demonstrated that osteoblast-associated lncRNAs play a vital role in modulating the TME.

EndMT plays a significant role in cancer for its association with a variety of cancer-associated pathways, including TGF-β, ET-1, NOTCH, CAV-1, Wnt, NOX4, and HIF-1α (Fig. 2) [108]. EndMT is regulated via numerous transcription factors (TFs), including SNAIL [109], SLUG [110], ZEB-1 [110], SIP-1 [110], TWIST [111], and LEF-1 [112,113]. These TFs can inhibit the expression of the genes involved in the cellular signaling process of adherens junctions and tight junctions. EndMT can result in the trans-differentiation of mesenchymal cells from ECs, which in turn differentiate into other stromal myofibroblasts/fibroblast/CAFs [108,114,115]. It has been shown that 40% of CAFs in the stroma compartment were formed through the EndMT process [116], and that CAFs secreted cytokines (such as TGF-β1) to promote metastasis and EMT in a variety of cancers [117]. LncRNA GATA6-AS negatively regulates lysyl oxidase homolog 2 (LOXL2), a suppressor of H3K4me3 methylation, to modulate endothe­ lial cell function through TGF-β2-induced EndMT [118]. EndMT of endothelial progenitor cells (EPCs) induced by TGF-β1 is coupled with the elevated expression of MALAT1, which modulates TGF-β1-induced EndMT via the signaling axis of MALAT1-miR-145-TGFBR2/SMAD3 [119]. Another study revealed that MALAT1 stimulates ox-LDLinduced EndMT via the Wnt/β-catenin signaling pathway [120]. MALAT1 is also involved in the regulation of high glucose-induced EndMT and fibrosis via repressing miR-145 expression and further promoting ZEB2 expression [121]. In a wide variety of cancers, miR-145 acts as a tumor suppressor that targets crucial oncogenic genes and proteins [122–124]. H19 inhibits glucose-regulated EndMT via regu­ lating the ERK/MAPK pathway instead of the TGF-β/SMAD axis [125]. The TF hypoxia-inducible factor-1 (HIF-1) induces the expression of growth factors in the endothelial portion to promote tumor

7. Association of lncRNAs with chondrocytes Chondrocytes, a major stromal component [25], are differentiated from MSCs [144]. The differentiation of MSCs to chondrocytes is regu­ lated by lncRNAs DANCR [145,146], HIT [147,148], ZBED3-AS1 [149], ROCR [150], and UCA1 [151]. UCA1 is expressed in human chon­ drocytes, while it is also expressed in various solid tumors [152]. It has been associated with several human malignancies. For example, the BMP9-induced upregulation of UCA1 modulates the proliferation and progression of bladder cancer cells [153]. UCA1 can promote the pro­ liferation and cisplatin chemoresistance in oral squamous cell carcinoma 6

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model, lnc-CHOP accumulation correlates positively with the generation of MDSCs to promote tumor growth [159]. Lnc-CHOP upregulation is associated with the increased expression of arginase-1, NO synthase 2, NADPH oxidase 2, and cyclooxygenase-2. In inflammatory and tumor environments, the overexpression of these enzymes is involved in the immunosuppressive function of MDSCs [159]. A murine model demonstrated the increased expression of lncRNA AK036396 in poly­ morphonuclear MDSCs, which enhanced the stability of ficolin B protein to cause the immunosuppression [160]. Inflammatory and tumorassociated factors may influence the upregulation of retinal noncoding RNA3 (RNCR3) in MDSCs [161]. Mechanically, RNCR3 pro­ motes Chop expression through sponging miR-185-5p during the MDSC

[154]. UCA1 is significantly upregulated in gastric cancer [155], and its upregulation is associated with poor prognosis in gastric cancer patients [152]. 8. Association of lncRNAs with myeloid-derived suppressor cells (MDSCs) Another major component of tumor stroma is MDSCs, a crucial immunosuppressor in the TME [156]. MDSCs are associated with the protumoral activity and inhibit immunotherapy response [157]. LncRNAs play a role in the regulation of MDSCs to modulate various cellular processes in diseases, including cancer [158]. In the murine

Fig. 3. The tumor-stroma crosstalk mediated by the lncRNAs encapsulated in cell-derived extracellular vesicles and exosomes. A. The CAF-tumor cell crosstalk cycle mediated by the lncRNAs transmitted through EVs/exosomes. B. The lncRNAs in tumor cells transferred to endothelial cells by EVs/exosomes to promote angiogenesis. 7

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differentiation, indicating the RNCR3/miR-185-5p/Chop axis involved in the immunosuppressive function of MDSCs [161]. The overexpression of miR-185-5p may improve the chemosensitivity of NSCLC to cisplatin via targeting ABCC1 [162] and induce apoptosis in prostate cancer by binding to the 3′ UTR region of BCL2L1 [163]. RNCR3 expression is associated with tumorigenesis, as shown in prostate cancer [164], GBM [165], glioma [166], and CRC [167]. Another lncRNA pseudogene, Olfr29-ps1, is expressed in MDSCs to promote the immunosuppressive function and regulate the differentiation of monocytic MDSCs in vitro and in vivo [168]. The Olfr29-ps1/miR-214-3p/MyD88 regulatory axis may promote the immunosuppressive function of MDSCs [168]. MiR214-3p acts as a tumor suppressor and improves the chemosensitivity via directly regulating ABCB1 and XIAP expression in retinoblastoma [169]. LncRNA PVT1 is overexpressed in granulocytic MDSCs in the hypoxic TME and its knockdown inhibits antitumor immune responses [170]. In summary, lnc-CHOP, Olfr29-ps1, PVT1, and RNCR3 are asso­ ciated with the immunosuppressive function and differentiation of MDSCs in cancer. In contrast, lnc-C/EBPβ may inhibit the immunosup­ pressive function of MDSCs in tumor and inflammatory environments [171]. Lnc-C/EBPβ is expressed in monocytic-MDSCs and polymorphonuclear-MDSCs of CRC patients. It interacts with C/EBPβ to enhance the molecular interaction of liver-enriched inhibitory protein with the liver-enriched activator proteins. The interaction prevents the function of LAP in the promoter regions of Arg-1, iNOS, NOX2, and COX2 and decreases the expression of these immunosuppressive enzymatic molecules [171]. RUNX1 overlapping RNA (RUNXOR) is another lncRNA, highly expressed in MDSCs from lung cancer tissue [172]. RUNXOR accelerates MDSC-mediated immunosuppression through downregulating its target RUNX1 in lung cancer. Besides, RUNXOR knockdown is related to decreased arginase-1 expression in MDSCs [172]. The knockdown of MALAT1 significantly increases the proportion of MDSCs in lung cancer [173]. LncRNA HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is expressed in MDSCs of lung cancer cells and its over­ expression enhances HOXA1 expression, thereby delaying tumor pro­ gression and activating the antitumor immune response via inhibiting the immunosuppression of MDSCs [174]. The expression levels of HOTAIR, PROM1, CCAT1, and MUC19 are inversely correlated with the enrichment of MDSCs in HPV-associated HNSCCs [175]. Collectively, these lncRNAs are associated with the biochemical activities of MDSCs in the TME.

the ECM signaling and stimulates invasion pathways in cancer [184]. Collagen 1 is a core ECM component with the tumor-promoting effect in the TME [185]. It can activate the expression of HOTAIR in lung adenocarcinoma cells, thereby promoting tumor progression [186]. MMPs have a substantial function in degrading the ECM and are involved in the invasion and metastasis of tumors [187]. Many lncRNAs can modulate the activity of lncRNAs [188–190]. For example, lncRNA SNHG5 overexpression can promote GSK3β expression through sponging miR-26a-5p and promote the expression of MMP2 and MMP9 to bolster HCC cell metastasis [188]. MiR-26a functions as a tumor suppressor in various cancers [191,192]. In HCC, lncRNA DLX6-AS1 is upregulated and plays an oncogenic role through the regulation of the DLX6-AS1/miR-203a/MMP2 signaling pathway [189]. DLX6-AS1 3’UTR is a potential target of miR-203a [189], which downregulates SNAI2 and inhibits EMT in ovarian cancer [193]. Another lncRNA ZFAS1 stimulates the hepatic invasion and intrahepatic and extrahepatic metastatic progression through modulating the miR-150/ZEB1/ MMP14/MMP16 signaling axis [190]. ZFAS1 activates the expression of ZEB1, MMP14, and MMP16 by binding miR-150 to abrogate its tumorsuppressive function [190]. 10. Association of lncRNAs with extracellular vesicles and exosomes in cancer Tumor and stromal cells can secrete extracellular vesicles (EVs) within the TME [36,194]. EVs increase the invasiveness of tumor cells by interacting with stromal cells [80]. In the TME, tumor and stromal cells secrete exosomes, which are involved in intercellular communication. EVs contain various regulatory molecules, including miRNA, lncRNA, mRNA, siRNA, DNA, and proteins, which are engulfed by communi­ cating with target cells in the TME [36]. Both EVs and exosomes are involved in the reprogramming of TME to aggravate tumor progression [195]. LncRNAs derived from EVs exert regulatory function in the TME and exhibit substantial signaling activities on targeting cells [196–198]. Exosomes contain lncRNAs, microRNAs, and circular RNAs [199]. In intercellular communication, regulatory lncRNAs are packaged into exosomes to act as signaling messengers (Fig. 3) [200], such as Exo1–4 and RMRP [201]. EV or exosome-associated lncRNAs may act as cancer biomarkers [202]. For example, EVs can mediate intercellular transferring and trafficking of functionally active lncRNA TUC339, which is involved in modulating tumor cell growth and adhesion in HCC [203]. CRC cellderived EV-enriched lncRNAs, including SNHG5, SNGH6, SNHG8, GAS5, LINC00493, TP53TG1, MIR4435-1HG, and H19, are involved in cancer prognosis and diagnosis [204]. The enrichment of HOTAIR in urinary bladder cancer patients’ urinary exosomes correlates with tumor initiation, progression, and poor prognosis [205]. The involvement of exosomes in the dynamic cross-talk between cancer cells and CAFs promotes cancer cell progression and metastasis via modulating the TME (Fig. 3A) [206,207]. The enrichment of H19 in CAF-derived exo­ somes can promote the β-catenin signaling, stemness, and chemo­ resistance of CRC cells [208]. In CRC, another CAFs-derived exosome transferring lncRNA CCAL functions in suppressing apoptosis, confer­ ring chemoresistance, and promoting the β-catenin signaling [209]. Fig. 3A illustrates that lncRNA lnc-CAF is transferred from tumor cells to CAFs via EVs/exosomes to activate interleukin-33 (IL-33) within the tumor stroma, which in turn enhances the activation of CAF markers, such as α-SMA, vimentin, and N-cadherin, the crucial molecules involved in cancer development [57]. Tumor-derived lncRNAs via exosomes are associated with the tumorstroma crosstalk and angiogenesis (Fig. 3B) [210]. LncRNA linc-POU3F3 is transferred from glioma cells to human brain microvascular ECs by exosomes to promote their migration, proliferation, angiogenesis, and tubule formation [211]. LncRNA linc-CCAT2 is highly expressed in the exosomes from glioma cells, which can transmit linc-CCAT2 to ECs to induce angiogenesis and inhibit apoptosis in the hypoxic condition.

9. Association of lncRNAs with extracellular matrix ECM is generated by stromal cellular populations within the TME and functions as a physical barrier blocking cancer cell invasion and metastasis [176]. To migrate to distant organs, abnormal cancer cells must travel through the ECM and invade into the vessels of lymphatic and circulatory systems. ECM is composed of approximately 300 different proteins, including enzymatic molecules for ECM modification, proteoglycans and glycoproteins for ECM stability, glycosaminoglycans, ECM bound growth factors, and other ECM-associated proteins and macromolecules [177]. Collagenases and matrix metalloproteases (MMPs) are core enzymatic molecules in degrading the ECM to facilitate cancer cell metastasis [178,179]. LncRNAs are involved in the tumorECM crosstalk in the TME. For example, lncRNAs play an important role in mediating ECM remodeling and turnover [180]. The ECMassociated lncRNA network modules are important in regulating key events in tumor progression [58]. H19 indirectly regulates TGFβ-induced protein, which is an ECM-associated protein capable of pro­ moting cancer cell progression and enhancing adhesion with ECMassociated proteins and macromolecules [181]. In esophageal squa­ mous cell carcinoma (ESCC), lncRNA-ECM overexpression can promote invasion, migration, and metastasis of ESCC cells by targeting ICAM1, a positive regulator of mesenchymal markers and a negative regulator of epithelial markers [182,183]. HOTAIR is involved in metastasis through 8

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Linc-CCAT2 controls the hypoxia-mediated angiogenesis and apoptosis in ECs by upregulating VEGFA, TGF-β, and Bcl-2 and downregulating Bax and caspase-3 (Fig. 3B) [212]. HOTAIR can be transferred into ECs by encapsulated into glioma cell-derived EVs [99]. In HCC, H19 involved in CD90+ cell-derived exosomes can stimulate ECs to form capillary networks by expressing pro-angiogenic factors, including VEGF, VEGFR1, and ICAM1 [198]. In epithelial ovarian cancer, exo­ somes secreted by cancer cells transmit MALAT1 to ECs to stimulate the proangiogenic activity by modulating angiogenesis-associated genes in ECs [213]. Exosomal lncRNAs are also associated with drug resistance in the tumor. For example, H19 packaged into exosomes can confer gefitinib resistance in EGFR-mutated NSCLC patients [214]. In breast cancer, the serum exosomal lncRNA-SNHG14 is overexpressed and associated with trastuzumab resistance by promoting the Bcl-2/Bax signaling cascade regulating apoptosis [215]. In estrogen receptor-positive breast cancers, UCA1 is transferred via exosomes to cause tamoxifen resistance [216]. Exosome-transmitted lncARSR can inhibit sunitinib response in renal cell carcinoma [217]. In malignant human hepatocytes, lnc-VLDLR at­ tenuates chemotherapy-induced cell death by transferred to HCC cells through the exosome-mediated mechanism [218].

example, lncRNA LNMAT1 is overexpressed in lymph node-metastatic bladder cancer [241] and LNMAT1 expression is correlated positively with the expression of M2 markers (CD206 and CD163) while negatively with M1 markers (HLA-DR and CD86). LNMAT1 can epigenetically upregulate CCL2, a crucial factor for recruiting TAMs infiltration into the TME, and upregulate VEGF-C to promote lymphangiogenesis and lymphatic metastasis in bladder cancer [241]. In breast cancer, lncRNA lnc-BM expression is associated with breast cancer brain metastases by regulating the STAT3-dependent expression of CCL2 to recruit macro­ phages in the brain. The recruited macrophages produce oncostatin M and IL-6 and activate the lnc-BM/JAK2/STAT3 pathway to stimulate breast cancer brain metastases [237]. LncRNA GNAS-AS1 is upregulated in ER-positive breast cancer tissue and M2 macrophages and its over­ expression inhibits miR-433-3p expression that in turn increases the expression of GATA3 [238]. That is, the GNAS-AS1/miR-433-3p/GATA3 axis stimulates the proliferation, migration, and invasion of ER-positive breast cancers by promoting the polarization of M2 macrophages [238]. LncRNA HISLA is upregulated in TAMs and is delivered to the breast cancer cells by EVs [239]. HISLA can prevent the degradation of HIF-1α via preventing the molecular interaction of PHD2 and HIF-1α that is responsible for the increased aerobic glycolysis, poor chemotherapeutic response, and shorter survival in breast cancer patients [239]. In breast cancer cells, the infiltration of macrophages leads to the upregulation of UCA1, which is involved in the invasiveness of breast cancer by pro­ moting AKT phosphorylation [242]. In HCC, HOTAIR overexpression promotes the secretion of CCL2, which is responsible for the recruitment of macrophages and MDSCs to the TME [243]. Within the TME in thy­ roid carcinomas, MALAT1 and FGF2 are highly expressed in M2 mac­ rophages and TAMs [240]. The secretion of MALAT1-induced FGF2 from TAMs inhibits the release of inflammatory cytokines, including TNF-α and IL-12, and stimulates the release of immunosuppressive cytokine IL-10 in the TME [240]. In cell-based M2 macrophage polari­ zation models, another angiogenesis-promoting lncRNA, lncRNAMM2P, are upregulated during the polarization of M2 macrophages but downregulated in M1 macrophages [244]. LncRNA-MM2P modu­ lates STAT6 phosphorylation, which is involved in the polarization of M2 macrophages. This molecular mechanism is responsible for macrophage-mediated modulation of tumorigenesis, tumor growth, and angiogenesis [244]. In summary, these studies indicate the significant association between lncRNAs and M2 macrophage polarization in TME that promotes tumor growth, invasion, metastasis, angiogenesis, lym­ phangiogenesis, and immune evasion in a wide variety of cancers.

11. Association of stromal lncRNAs with the tumor immune microenvironment The tumor immune microenvironment, composed of immunological mediators, such as chemokines, cytokines, and growth factors, creates a crucial network of cellular communication between cancer and stromal cells. In the TME, lncRNAs are capable of provoking the release of chemokines to promote the metastatic potential of cancer cells [54]. The crosstalk between regulatory lncRNAs and the TGF-β pathway has been shown in cancers, evidenced by that lncRNAs targeting the regulatory components of the TGF-β pathway are activated [219]. In the CAFs from NSCLC tissues, the TGF-β/SMAD pathway upregulates the TGFβ-acti­ vated lncRNA TBILA, which in turn promotes the NSCLC progression [220]. In cholangiocarcinoma, another TGFβ-induced lncRNA TLINC, is associated with increased proinflammatory cytokines, elevated EMT, and metastatic phenotype [221]. LncRNAs may control IL-6-associated immune signaling and molecular functions that are involved in cancer development, invasion, angiogenesis, migration, and metastasis [222–224]. IL-6 can activate many lncRNAs in cancer, e.g., IL-6/STAT3induced lncRNA TCF7, which promotes the aggressiveness of HCC via the EMT [225]. Also, IL-6 can inhibit certain lncRNAs in cancer. For example, the IL-6/STAT3/miR-21 signaling cascade can substantially downregulate the lncRNA PCAT29 in prostate cancers [226]. LncRNA TSLNC8, a tumor suppressor on chromosome 8p12, is downregulated in HCC as a consequence of the dysregulation of the TSLNC8-transketolaseSTAT3 axis [227]. The lncRNAs of MDSCs, including RNCR3 [161], Olfr29-ps1 [168], RUNXOR [172], and HOTAIRM1 [174], are associated with the immu­ nosuppression in the TME. Also, lncRNAs TBILA [220], Lethe [228], ZEB2NAT [48], CASC9 [49], and LINC00092 [54] are related to the CAFs-mediated tumorigenesis through regulating the TME (Table 1). In addition to MDSCs and CAFs, another immunosuppressive component in the TME is tumor associated macrophages (TAMs), which play key roles in tumor progression, invasion, metastasis, chemoresistance, and im­ mune evasion [229,230]. M1 macrophages are anti-tumorigenic, while M2 macrophages are pro-tumorigenic [231–233]. LncRNAs regulate TAMs by affecting the polarization, epigenetics, and classic signaling pathways as well as by other regulatory mechanisms [234]. The lncRNA RP11-389C8.2 was overexpressed in M2 macrophages and facilitated their differentiation via the PKA/CREB pathway [235]. HCC-derived exosomes contain abundant lncRNA TUC339 involved in the regula­ tion of macrophages’ activation [236]. TAMs-associated lncRNAs play crucial immunosuppressive roles by promoting macrophage polarization in the TME [237–244]. For

12. Association of stromal lncRNAs with therapeutic resistance in cancer LncRNAs, including stroma-associated lncRNAs, have been associ­ ated with drug resistance in cancer [245–247]. For example, lncRNA PCAT-1 is involved in chemoresistance, immunosuppression, and remodeling of tumor stroma in lung cancer [248]. Mechanistically, PCAT-1 modulates Kras-mediated lung cancer chemoresistance through immunosuppressive miR-182/miR-217 signaling and p27/CDK6 regu­ lation [248]. Besides, PCAT-1 overexpression promotes the cisplatinresistance in esophageal cancer by inhibiting apoptosis [249] and in gastric cancer by increasing ZEB1 [250]. PCAT-1 decreases the sensiti­ zation of CRC cells to the 5-fluorouracil via modulating MYC expression [251]. Another lncRNA CCAL can promote oxaliplatin resistance in CRC through activating the β-catenin pathway [252]. H19 is associated with oxaliplatin resistance of CRC cells via sponging miR-141 to activate the β-catenin pathway [208]. H19 is also dysregulated in various stromal components, including MSCs, EC, and ECM (Table 1). Many studies have indicated that H19 is related to drug resistance in cancer, including doxorubicin resistance of breast cancer cells through the cullin4A-MDR1 pathway [253], 5-fluorouracil resistance of CRC cells by enhancing SIRT1-mediated autophagy [254], cisplatin resistance in seminoma via sequestering miRNA-106b-5p [255, and bortezomib resistance of 9

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Table 2 Association of stromal lncRNAs with therapeutic resistance in cancer. LncRNA

Associated stromal components

Regulatory status of lncRNA

Cancer type

Therapeutic agent

Molecular mechanism

Reference

PCAT-1

CAFs

Up

Chemoresistance

Increase the miR-182/miR-217 signaling and p27/CDK6

[248]

CCAL DNM3OS ANRIL

CAFs CAFs CAFs

Up Up Up

Lung cancer CRC ESCC OSCC

Oxaliplatin Radioresistance Cisplatin

H19

CAFs

Up

CRC

Oxaliplatin

Activate the β-catenin pathway Regulate the DNA damage response Promote the drug transporters MRP1 and ABCC2 and mediate the abnormal efflux of cisplatin Sponge miR-141 and activate the β-catenin pathway

HCP5

MSC

Up

MACC1AS1

MSC

Up

Gastric cancer Gastric cancer

5-fluorouracil and oxaliplatin 5-fluorouracil and oxaliplatin

Facilitate the fatty acid oxidation via the miR-3619-5p/ AMPK/PGC1α/CEBPB axis Promote the fatty acid oxidation and antagonize miR145-5p

[252] [257] [258] [258] [253] [208] [259] [259] [261] [261]

Fig. 4. Flowchart showing how dysregulated lncRNAs in the tumor stroma contribute to tumor progression, invasion, metastasis, and drug resistance. TME: tumor microenvironment.

myeloma cells by targeting MCL-1 [256]. CAFs promote the expression of lncRNA DNM3OS to significantly increase the radioresistance by influencing DNA damage response [257]. In the TME, dysregulation of lncRNA ANRIL is associated with the upregulation of drug transporter proteins MRP1 and ABCC2 to stimulate cisplatin resistance of tumors [258]. LncRNA HCP5 is upregulated in gastric cancer (GC) and is associated with the chemoresistance and stemness of GC [259]. Besides, HCP5 is involved in the development of gemcitabine-resistance in pancreatic cancer via the miR-214-3p/HDGF axis [260]. LncRNA MACC1-AS1 can promote fatty acid oxidation and stimulate stemness and chemoresistance through antagonizing miR-145-5p [261]. LncRNA MALAT1 is aberrantly expressed in various components of tumor stroma, including CAFs, ECs, osteoblasts, and TAMs (Table 1). MALAT1 is involved in cisplatin resistance of bladder cancer through the miR101-3p/VEGF-C pathway [262], docetaxel resistance of lung adeno­ carcinoma by upregulating E2F3 and ZEB1 [263], cisplatin resistance of gastric cancer by suppressing the miR-30b/ATG5 axis, temozolomide resistance of glioblastoma by regulating miR-101, docetaxel resistance of prostate cancer through the MALAT1/miR-145-5p/AKAP12 axis [264], and oxaliplatin resistance of CRC [265]. To summarize, these previous studies demonstrated the significant association of stromal lncRNAs with drug resistance in cancer. Table 2 shows the association of stromal lncRNAs with therapeutic resistance in cancer.

13. Concluding remarks Tumor stromal cells can stimulate the oncogenic phenotypes of other cellular populations in the TME via abnormal cellular signaling medi­ ated by dysregulated lncRNAs (Fig. 4). Numerous lncRNAs are involved in cancer initiation, progression, and metastasis by participating in aberrant cellular signaling pathways in tumor stroma (Table 1). For conquering cancer, in addition to tumor cells, tumor stroma-associated oncogenic and tumor-suppressive molecules could be promising tar­ gets, including ECM, tumor stroma-specific proteins, tumor-stroma crosstalk, and tumor stromal antigens. Because of the important roles of lncRNAs in modulating tumor cells and tumor stroma, lncRNAs could be potentially useful targets for cancer therapy, although an in-depth investigation into the biology of lncRNAs in the tumor and tumor stroma is necessary. CRediT authorship contribution statement MNU and XW conceived the review, designed the study, and wrote the manuscript. Both authors read and approved the final version of the manuscript.

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Funding [22]

This work was funded by China Pharmaceutical University (grant number 3150120001 to XW). Declaration of competing interest Both authors declare that they have no competing interests. Acknowledgement We thank Dr. Suman Mohajan from Louisiana State University Health Sciences Center for editing the manuscript. References [1] J.T. Lee, Epigenetic regulation by long noncoding RNAs, Science 338 (2012) 1435–1439, https://doi.org/10.1126/science.1231776. [2] ENCODE Project Consortium, The ENCODE (ENCyclopedia of DNA Elements) project, Science 306 (2004) 636–640, https://doi.org/10.1126/science.1105136. [3] W.F. Doolittle, Is junk DNA bunk? A critique of ENCODE, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 5294–5300, https://doi.org/10.1073/pnas.1221376110. [4] A. Salviano-Silva, S.C. Lobo-Alves, R.C. de Almeida, D. Malheiros, M.L. PetzlErler, Besides pathology: long non-coding RNA in cell and tissue homeostasis, Non-Coding RNA 4 (2018), https://doi.org/10.3390/ncrna4010003. [5] J.T. Lee, N. Lu, Targeted mutagenesis of Tsix leads to nonrandom X inactivation, Cell 99 (1999) 47–57. [6] W. Zhuang, X. Ge, S. Yang, M. Huang, W. Zhuang, P. Chen, X. Zhang, J. Fu, J. Qu, B. Li, Upregulation of lncRNA MEG3 promotes osteogenic differentiation of mesenchymal stem cells from multiple myeloma patients by targeting BMP4 transcription, Stem Cells Dayt. Ohio. 33 (2015) 1985–1997, https://doi.org/ 10.1002/stem.1989. [7] E.A. Gibb, C.J. Brown, W.L. Lam, The functional role of long non-coding RNA in human carcinomas, Mol. Cancer 10 (2011) 38, https://doi.org/10.1186/14764598-10-38. [8] J.R. Prensner, A.M. Chinnaiyan, The emergence of lncRNAs in cancer biology, Cancer Discov 1 (2011) 391–407, https://doi.org/10.1158/2159-8290.CD-110209. [9] S. Ning, J. Zhang, P. Wang, H. Zhi, J. Wang, Y. Liu, Y. Gao, M. Guo, M. Yue, L. Wang, X. Li, Lnc2Cancer: a manually curated database of experimentally supported lncRNAs associated with various human cancers, Nucleic Acids Res. 44 (2016) D980–D985, https://doi.org/10.1093/nar/gkv1094. [10] S.E. Wojcik, S. Rossi, M. Shimizu, M.S. Nicoloso, A. Cimmino, H. Alder, V. Herlea, L.Z. Rassenti, K.R. Rai, T.J. Kipps, M.J. Keating, C.M. Croce, G.A. Calin, NoncodingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancer, Carcinogenesis 31 (2010) 208–215, https://doi.org/10.1093/ carcin/bgp209. [11] L.A. Hindorff, P. Sethupathy, H.A. Junkins, E.M. Ramos, J.P. Mehta, F.S. Collins, T.A. Manolio, Potential etiologic and functional implications of genome-wide association loci for human diseases and traits, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 9362–9367, https://doi.org/10.1073/pnas.0903103106. [12] T.R. Mercer, M.E. Dinger, J.S. Mattick, Long non-coding RNAs: insights into functions, Nat. Rev. Genet. 10 (2009) 155–159, https://doi.org/10.1038/ nrg2521. [13] C.P. Ponting, P.L. Oliver, W. Reik, Evolution and functions of long noncoding RNAs, Cell 136 (2009) 629–641, https://doi.org/10.1016/j.cell.2009.02.006. [14] A.M. Khalil, M. Guttman, M. Huarte, M. Garber, A. Raj, D. Rivea Morales, K. Thomas, A. Presser, B.E. Bernstein, A. van Oudenaarden, A. Regev, E.S. Lander, J.L. Rinn, Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 11667–11672, https://doi.org/10.1073/pnas.0904715106. [15] T. Gutschner, S. Diederichs, The hallmarks of cancer: a long non-coding RNA point of view, RNA Biol. 9 (2012) 703–719, https://doi.org/10.4161/rna.20481. [16] W.-X. Peng, P. Koirala, Y.-Y. Mo, LncRNA-mediated regulation of cell signaling in cancer, Oncogene 36 (2017) 5661–5667, https://doi.org/10.1038/onc.2017.184. [17] A.M. Schmitt, H.Y. Chang, Long noncoding RNAs in cancer pathways, Cancer Cell 29 (2016) 452–463, https://doi.org/10.1016/j.ccell.2016.03.010. [18] M. Huarte, The emerging role of lncRNAs in cancer, Nat. Med. 21 (2015) 1253–1261, https://doi.org/10.1038/nm.3981. [19] Y. Kotake, T. Nakagawa, K. Kitagawa, S. Suzuki, N. Liu, M. Kitagawa, Y. Xiong, Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene, Oncogene 30 (2011) 1956–1962, https://doi.org/10.1038/onc.2010.568. [20] D. Khaitan, M.E. Dinger, J. Mazar, J. Crawford, M.A. Smith, J.S. Mattick, R. J. Perera, The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion, Cancer Res. 71 (2011) 3852–3862, https://doi.org/ 10.1158/0008-5472.CAN-10-4460. [21] R.A. Gupta, N. Shah, K.C. Wang, J. Kim, H.M. Horlings, D.J. Wong, M.-C. Tsai, T. Hung, P. Argani, J.L. Rinn, Y. Wang, P. Brzoska, B. Kong, R. Li, R.B. West, M. J. van de Vijver, S. Sukumar, H.Y. Chang, Long non-coding RNA HOTAIR

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