LncRs are more than 200 bases long and are species/tissue specific. LncRs can interact with DNA, RNA, and proteins to regulate a wide range of biological processes [149,150]. Recent microarray analyses and next-generation sequencing assays have found that lncRs can modulate gene expression at multiple levels, including regulation at the epigenetic, transcriptional, and post-transcriptional levels. In addition, lncRs can act as sponges or molecular decoys for miRs, and reduce a population of valid specific miR, and thus, influence miR activity.There are two major categories of lncRs, which are defined as oncogenic lncRs such as MALAT1, HOTAIR, SOX2-OT and H19, and tumor suppressing lncRs such as MEG3, PANDAR, GAS5, and TUG1 according to their pathological features [151]. Evidence is accumulating that dietary polyphenols including six polyphenols can modulate lncRs. Table 4 shows the modulations of lncRs by six polyphenols. The possible contribution of these lncRs to RSTAPs is shown in Figure 1. 3.2. lncR Modulations by CUR

AK294004

In nasopharyngeal carcinoma (NPC) cell lines (CNE-2), a microarray analysis showed that expression of a number of lncRs was changed by X-ray irradiation and that the expression of 116 ncRNAs was restored by CUR [156]. The results of qRT-PCR confirmed these changes in six lncRs (AF086415, AK095147, RP1-179N16.3, MUDENG, AK056098 and AK294004). Functional studies suggested that cyclin D1 is a direct target of AK294004. Radiotherapy is one of the most effective treatment modalities for NPC patients, and radioresistance is the main risk factor contributing to poor prognosis. This resistance occurs with the first X-ray treatment and the survived cells become more resistant to the second X-ray treatment, leading to invalidation of the treatment. Thus, CUR can be expected to improve radiosensitivity by altering expression of these lncRs.

GAS5

Dendrosomal CUR treatment of MCF7, MDA-MB231 and SKBR3 cells increased the expression of Tusc7 and GAS5 [157]. GAS5 downregulation suppressed many anticancer effects of dendrosomal CUR in breast cancer (BCa) cells. Because an amplified level of GAG5 has been reported to reduce chemotherapy resistance [158], Co-treatment of dendrosomal CUR with GAS5 overexpression could be a clinically useful tool against drug-resistant BCa cells.

H19

Kujundzić et al. [159] found that CUR inhibited cell proliferation and suppressed expression of lncR H19 in several human cancer cell lines such as HCT 116, SW 620, and HeLa. CUR’s downregulation of H19 expression was not found in primary normal thyroid cells [159]. Similarly, Liu et al. [160] found that CUR inhibited the proliferation of gastric cancer (GCa) SGC-7901 cells, suppressed H19 expression, and increased p53 expression. Ectopic expression of H19 attenuated CUR-induced apoptosis and downregulated p53 expression. CUR downregulated the expression of c-Myc oncogene and addition of c-Myc protein in the cell culture medium attenuated the CUR-induced downregulation of H19 expression, which may explain part of the anticancer mechanism of CUR.In tamoxifen-resistant MCF-7 BCa cells, CUR decreased the expression levels of the epithelial marker E-cadherin, increased the expression levels of mesenchymal marker N-cadherin, and decreased H19 expression [161]. Overexpression of H19 induced EMT, invasion and migration by upregulating Snail, a key regulator of the EMT process. CUR attenuated H19-induced alterations in N-cadherin and E-cadherin expression levels and inhibited H19-induced invasion and migration, indicating that CUR may prevent H19-associated cancer cell metastasis.

KCNQ1OT1

The cisplatin-resistant colorectal cancer (CRC) HCT8/DDP cells exhibited higher expression levels of oncogenic KCNQ1OT1 compared to non-resistant cells. Zheng et al. [162] found that CUR promoted apoptosis in HCT8/DDP cells and silencing of KCNQ1OT1 enhanced apoptosis in the cisplatin-resistant cells. KCNQ1OT1 was found to eliminate the suppressive effect of miR-497 on expression of anti-apoptotic Bcl-2. KCNQ1OT1 overexpression counteracted the effect of CUR on these cells via miR-497/Bcl-2 axis. CUR downregulated KCNQ1OT1 expression, leading to suppression of cisplatin resistance. This may explain CUR’s reducing effect on cisplatin resistance.

LINC00691

In papillary thyroid cancer B-CPAP cells, CUR decreased cell proliferation, promoted apoptosis, and inhibited LINC00691 expression [163]. CUR administration or transfection of si-LINC00691 caused downregulation of AKT leading to apoptosis in these cells, suggesting that inhibition of LINC00691 is involved in the anticancer effect of CUR.

linc-PINT

Microarray experiments with acute lymphoblastic leukemia cells from the patients showed that 43 lncRs were aberrantly expressed as compared to healthy donor blood cells [164]. qRT-PCR found that 15 out of the 16 tested lncRs examined had the same expression pattern in the expression array including downregulation of linc-PINT. Overexpression of this lncR in Molt-4 cells induced the transcription of HMOX1, which reduced cell viability. CUR was found to upregulate the expression of linc-PINT and HMOX1 in Molt-4 cells, suggesting that upregulation of linc-PINT may be one of the CUR’s anticancer mechanisms.

MEG3

Alghanimi and Ghasemian [165] showed that dendrosomal CUR promoted cell death in BCa MCF-7 cells, increased gene expression of lncR MEG3, and decreased expression of FOXCUT gene. Since previous studies have shown that overexpression of MEG3 is associated with inhibition of cancer cell growth [166], CUR’s upregulation of this lncR may contribute to its anticancer effects. CUR induced apoptosis of gemcitabine-resistant non-small cell lung cancer (NSCLC) cell lines A549/GR and H520/GR and upregulated the expression of MEG3 and PTEN [167]. MEG3 overexpression increased PTEN expression and knockdown of MEG3 decreased its expression. MEG3 knockdown or PTEN knockdown mitigated CUR’s effects on these cells.

NRB2

Yu et al. [168] found that CUR upregulated lncR NBR2 in CRC cell lines including HCT116, HCT8, SW620, and SW480, and inhibited CRC cell proliferation by activating the AMPK pathway and inactivating mTOR. These effects of CUR were cancelled by knockdown of NBR2, indicating that modulation of the NBR2/AMPK/mTOR pathway may be involved in the anticancer effects of CUR.

PANDAR

CUR increased PANDAR expression in CRC DLD-1 cells and silencing of PANDAR increased apoptosis and attenuated cell senescence by stimulating expression of PUMA [169]. Knockdown of PANDAR switched CUR-induced senescence to apoptosis, suggesting the usefulness of CUR in CRC therapy. Since PUMA has been reported to initiate apoptosis by dissociating Bax and Bcl-X(L), leading to activation of proapoptotic function of Bax [170], it may be speculated that CUR-mediated upregulation of PANDAR may involve in the anticancer effect of CUR via Bax activation.

PVT1

The EZH2, a subunit of polycomb repressive complex 2 (PRC2), is known to have an important role in drug resistance. EZH2 interacts with several lncRs including PVT1 to modulate EMT and cancer stemness related to drug resistance. Yoshida et al. [171] found that CUR sensitized chemoresistant cancer cells by inhibiting the expression of EZH2 and PVT1 using gemcitabine-resistant pancreatic ductal adenocarcinoma cells, suggesting that CUR can overcome chemoresistance in pancreatic ductal adenocarcinoma patients via inhibition of the PRC2-PVT1-c-Myc axis.

ROR

Shao et al. [172] demonstrated that CUR inhibited the cell growth of human hepatoma SMMC7721 and Huh-7 cells through inducing cell cycle arrest and apoptosis and downregulated ROR expression. Overexpression of ROR restored CUR-induced growth inhibition and inactivated Wnt/β-catenin signaling, suggesting that downregulation of ROR is involved in the anticancer effects of CUR.In CD44+/CD133+ human prostate cancer (PCa) stem cells derived from the PCa cell lines Du145 and 22RV1, CUR treatment resulted in the inhibition of cell growth and invasion, and cell cycle arrest along with decreased expression of stem cell marker proteins such as Oct4 [37]. In addition, high miR-145 expression and suppression of ROR expression were observed in the CUR-treated cells. Bioinformatic analysis and luciferase activity assays showed that Oct4 and ROR directly compete for miR-145 binding. Thus, CUR’s anticancer activity involves its downregulation of ROR which functions as miR sponge to competitively bind tumor suppressing miR-145, contributing to an increase in the population of miR-145, resulting in downregulation of Oct4, which plays a critical role in cancer development and progression [8,173].

UCA1

In A549 cells, CUR inhibited cell proliferation and cyclin D1 expression, and enhanced cell apoptosis [174]. CUR inhibited UCA1 expression, leading to downregulation of Wnt/mTOR pathway. Overexpression of UCA1 attenuated the effect of CUR on apoptosis. Based on previous findings that knockdown of UCA1 reduces c-Myc expression [175], CUR’s anticancer effect may be associated with downregulation of c-Myc via downregulation of UCA1.

XIST

Sun et al. [176] found that XIST was downregulated in renal cell carcinoma (RCC) tissues and cells such as ACHN, Caki-1, Caki-2, and 786-O. Overexpression of XIST suppressed cell proliferation, induced cell cycle arrest at G0/G1 in cultured cells, and inhibited tumor growth in a xenograft model. XIST directly interacted with miR-106b-5p and increased p21 expression. CUR regulated XIST/miR-106b-5p/p21 axis in RCC cells, indicating a role of XIST in RCC. 3.3. lncR Modulations by EGCG

AF085935

Sabry et al. [177] showed that the combination of EGCG and metformin was highly effective against the proliferation of hepatoma HepG2 cells. This combination downregulated AF085935 and glypican-3 and promoted apoptosis via upregulation of caspase 3 and downregulation of survivin. However, the direct target of AF085935 has not yet been identified.

LINC00511

Zhao et al. [111] found that EGCG modulated the expression of a number of lncRs in GCa AGS and SGC7901 cells. EGCG suppressed oncogenic LINC00511 and knockdown of LINC00511 inhibited cell proliferation and promoted cell death. LINC00511 could decrease the expression of miR-29b, followed by inducing GCa development. Knockdown of miR-29b rescued the effects of LINC00511 silencing. Overexpression of KDM2A, a target of miR-29b, restored the level of LINC00511.

NEAT1

CTR1 is known to promote cisplatin internalization in tumor cells. Jiang et al. [135] found that EGCG induced CTR1 and enhanced cisplatin sensitivity in NSCLC cells. miR-98-5p suppressed CTR1 gene expression, while NEAT1 enhanced it. Bioinformatics analysis showed that miR-98-5p is a target of CTR1. NEAT1 can be a competing endogenous lncR that upregulates EGCG-induced CTR1 by sponging miR-98-5p in these cells, suggesting that EGCG is an effective chemotherapeutic agent in the lung cancer treatment. Similarly, Chen et al. [178] found that EGCG increased ROS levels, expression of CTR1 and NEAT1 in tumor tissue, and suppressed ERK1/2 and p-ERK1/2 in a nude mouse xenografts model of lung cancer.Cancer stem cells have been implicated as a major player in tumor metastasis, tumor recurrence, and chemotherapy resistance. CTR1 is associated with cisplatin resistance. Jiang et al. [179] found that in cancer stem cell-rich cells derived from parent lung cancer NSCLC cells, NEAT 1 was upregulated and CTR1 was downregulated. EGCG downregulated NEAT1 and suppressed the stemness triggered by overexpressing NEAT1 via inducing CTR1 expression. Wnt signaling pathway and EMT process were shown to be involved in NEAT1-induced cancer cell stemness in NSCLC.

SOX2OT variant 7

Wang et al. [180] found the synergistic effect of EGCG with an antitumor drug doxorubicin on osteosarcoma cells. EGCG targeted SOX2OT variant 7 via Notch3 signaling pathway and decreased stemness including drug resistance, tumorigenic ability, and self-renewal ability of these cells.

Other studies

The results of lncR microarray analysis revealed that EGCG treatment of lung cancer cells caused significant alterations in a total of 960 lncRs and 1434 mRNAs [181]. Among them, upregulation of five lncRs (ENSG00000272796.1, ENSG00000254054.2, ENSG00000260630.2; SNAI3-AS1, ENSG00000235142.2; LINC0532 and ENSG00000224063.1; CALCRL-AS1) and downregulation of five lncRs (ENSG00000251018.2, ENSG00000226403.1, PSMC3IP, ENSG00000230109.1 and SG00000130600.10) were confirmed by qRT-PCR. Bioinformatic analysis suggests that potential anticancer mechanisms by which EGCG regulates lncRs are associated with RSTAP members such as AKT1, caspase 3, and p53 and others, but the individual targets of these lncRs remain to be determined. 3.5. lncR Modulations by QUE

MALAT1

By data mining including computational analysis, Li et al. [187] identified QUE’s therapeutic candidate genes in cervical cancer HeLa cells. Among them, EGFR, JUN, AR, CD44, and MUC1 were selected, and MALAT1, 10 miRs, and 71 circRs upstream of these genes were determined. These findings lead to the construction of a regulatory network of lncR/circR-miR-mRNA pathway and provided a theoretical basis for targeted therapy of cervical cancer. In PCa PC-3 cells, QUE downregulated the expression of oncogenic MALAT1 and inhibited the growth of these cells and their xenograft tumors [188]. QUE suppressed the EMT process, promoted apoptosis, and downregulated PI3K/AKT signaling pathway. Overexpression of MALAT1 attenuated the QUE’s effects.QUE treatment decreased the cell viability of HUVEC cells and downregulated the expression of MALAT1 and MIAT [189]. Since MALAT1 is related to endothelial cell growth, metastasis, and angiogenesis and since MIAT regulates angiogenesis through interaction with miR-150-5p, which can target VEGF, QUE may exert its anticancer effects through downregulation of these lncRs.

NEAT1

Sheng et al. [190] found that in a mouse model of acute pancreatitis, QUE downregulated TNF-α, IL-6, and IL-10, while upregulating miR-216b expression, leading to suppression of p38 MAPK signaling pathway. QUE downregulated NEAT1 which is a direct target of miR-216b. NEAT1 was shown to be a direct target of miR-216b and the triad of NEAT1, miR-216b, and MAP2K6 formed a competitive endogenous RNA network. These findings may partially explain QUE’s anticancer effects.

SNHG7

Chai et al. [119] found NSCLC cells had the elevated expression of oncogenic SNHG7 and the decreased expression of miR-34a-5p compared to those in normal cells. QUE downregulated SNHG7 and increased miR-34a-5p levels in these cells. Overexpression of SNHG7 or downregulation of miR-34a-5p promoted NSCLC cell growth and metastasis. The anticancer effects of QUE were counteracted by co-transfection of SNHG7 mimic or miR-34a-5p inhibitor. These results indicate that QUE may exert its anticancer effects by mediating signaling via the SNHG7/miR-34a-5p axis. Based on the previous findings that SNHG7 upregulates AKT/mTOR pathway in NSCLC cells [191], it is plausible that QUE’s downregulation of SNHG7 is related to downregulation of this pathway.

UCA1

In BCa MCF-7 cells, QUE inhibited cell proliferation and induced cell cycle arrest at G2 phase [192]. INXS is a lncRNA that is able to shift the Bcl-X alternative splicing from the anti-apoptotic Bcl-XL to the pro-apoptotic Bcl-XS, and QUE can cause INXS upregulation and UCA1 downregulation in BCa cells, suggesting QUE exerts its anticancer effects through modulation of these lncRs. 3.6. lncR Modulations by RES

AK001796

Yang et al. [193] found that AK001796 was overexpressed in lung cancer tissues and cells (A549 and H446) and its expression was downregulated in RES-treated lung cancer cells. Knockdown of AK001796 reduced cell viability and caused a cell cycle arrest at G0/G1.

DLEU2

Kay et al. [194] demonstrated that RES upregulated the tumor suppressor gene DLEU2 in 11 alternative splicing transcripts. Since DLEU2 was shown to negatively regulate cyclins E1 and D1 through upregulation of miR-15a/miR-16-1 and since overexpression of DLEU2 recovered cellular proliferation and inhibition of the colony-forming ability of tumor cells in a miR-15a/miR-16-1-dependent manner [195], RES’s upregulation of DLEU2 may contribute to its anticancer effects.

H19

In GCa SGC7901 cells, 200 µM RES was shown to increase expression of MEG3, PTTG3P and BISPR and decreased expression of GAS5 and H19 [196]. RES at 50 µM upregulated H19 and MALAT1, and knockdown of H19 in RES-treated cells increased the effect of RES on apoptosis, endoplasmic reticulum stress, and cell cycle S-phase arrest in these cells, suggesting that RES increases chemotherapy sensitivity.

MALAT1

RES inhibited invasion and metastasis of CRC LoVo cells and downregulated MALAT1 [197]. RES’s suppressive effects on tumor cell migration and invasion and protein expression of β-catenin, c-Myc, and MMP-7 were attenuated by overexpression of MALAT1. The finding suggests that suppression of Wnt/β-catenin signaling by downregulation of MALAT1 contributes to RES’s anticancer effects.

NEAT1

Geng et al. [198] found higher expression of NEAT1 in multiple myeloma U266 and LP-1 cells compared to normal bone marrow plasmocytes. RES downregulated NEAT1 and counteracted enhanced cell proliferation, migration, and invasion induced by NEAT1 overexpression. NEAT1 overexpression upregulated the expression of nuclear β-catenin, c-Myc, MMP-7 and survivin, leading to activation of the Wnt/β-catenin signaling pathway.

PCAT29

RES upregulated PCAT29 expression and attenuated its downregulation induced by IL-6 [199]. Knockdown of PCAT29 expression increased cell viability, while RES-induced upregulation of PCAT29 resulted in decreased cell viability. Since RES can downregulate IL-6 (Figure 1), RES may exert its anticancer effect by upregulating PCAT29 expression. Since PCAT29 has been reported to upregulate PTEN by downregulation of miR-494 in NSCLC [200], upregulation of PCAT29 can be reasonably related to anticancer activity of RES.

Other studies

In glioma U87 and U251 cells, RES upregulated NEAT1, MIR155HG, MEG3, and ST7OT1 during induction of apoptosis [201]. Since NEAT1 and MIR155HG are oncogenic [202,203,204] and MEG3 is tumor-suppressing [166], the effect of RES on MEG3 may be a predominant contributor to apoptosis of these cells. NEAT1 was demonstrated to activate ERK, which is a component molecule in RSTAPs (Figure 1) [202].In colon adenocarcinoma HT-29 cells, the results of qRT-PCR indicated that RES decreased the expression of CCAT1, CRNDE, H19, HOTAIR, PCAT1, PVT1, and SNHG16, and upregulated CCAT2, MALAT1, and TUSC7 [205]. Although individual roles of these lncRs in RES’s anticancer effects are not clear, for example, downregulation of HOTAIR may be related to anticancer effects, since better disease-free survival rate was observed in colon adenocarcinoma patients with low HOTAIR expression. It may be considered that RES’s downregulation of CCAT1 contributes to the anticancer effect, because CCAT1 promotes tumor progression by stabilizing PI3K/AKT/mTOR signalling in lung adenocarcinoma [206].