Non-protein coding RNAs have emerged as a regulator of cell signaling and cancer progression through regulation of cell proliferation, metastatic burden, and cancer stem cell capacity. A subtype of non-protein coding RNA is long non-protein coding RNA (lncRNA). Besides their aforementioned roles in cancer cell biology, dysregulation of lncRNAs contribute to resistance to therapeutic treatments. A couple of important therapeutic classes are chemotherapy and targeted/hormone therapies. This review highlights the variety of malignancies affected by lncRNA dysregulation and the underlying mechanism causing therapeutic resistance.
Cancer treatment has advanced a great deal over time with the introduction of targeted therapy, improved surgical procedures, precise radiotherapy, and continual development of chemotherapy. Cancer therapy discoveries first began in the 1940’s, with the development of methotrexate[
Cancer can attain drug resistance through acquired and intrinsic factors. Intrinsic factors consist of endogenous gene dyregulation, thus cancer cells are able to avoid cell toxicity when under cancer treatment. Acquired factors are activated after administration of drug treatment causing the remaining viable cells to develop a molecular perturbation which induces these cells to develop therapeutic resistance. Intrinsic and acquired factors attained within the tumor and/or in the tumor microenvironment can cause reduction in the cancer’s sensitivity to therapeutics[
Non-protein coding RNA (ncRNA) is a subclass of RNA previously considered as non-functional RNA based upon the idea that ncRNA lacks a cellular function[
LncRNAs are 200 or more base pairs in length[
lncRNAs with the capability of perturbing chemotherapeutic resistance
lncRNA | Level of lncRNA in therapeutic resistant state | Cancer | Therapeutic agent | Mechanism of action | Ref. |
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ARSR | Upregulated | Liver | Doxorubicin | Binding to PTEN mRNA causing degradation of PTEN mRNA leading to enhancement of PI3K/AKT | [ |
ATB | Upregulated | Breast | Trastuzumab | Binding to miR-200c modulates ZEB1 and ZNF1 expression | [ |
BCAR4 | Upregulated | Breast | Tamoxifen | Phosphorylates ERBB2 and ERBB3 leading to activation of AKT kinase 1/2 | [ |
CASC2 | Downregulated | Gastric | Cisplatin | Sponging of miR-19a thus decreasing apoptosis | [ |
FAM84B-AS | Upregulated | Gastric | Cisplatin | Preventing Bax translocation from cytoplasm to mitochondria and keeping cytochrome C from releasing in mitochondria thus reduction of apoptosis | [ |
FOXC2-AS1 | Upregulated | Osteosarcoma | Doxorubicin | Acting on ABCB1 | [ |
FOXD2-AS1 | Upregulated | Bladder | Gemcitabine | Sponging of miR-143 leading to upregulation of ABCC3 | [ |
GAS5 | Downregulated | Breast | Trastuzumab | Interacting with miR-21 increasing PTEN | [ |
GBCDRlnc1 | Upregulated | Gallbladder | Doxorubicin | Interacting with PGK1 prevents PGK1 ubiquination leads to subsequent enhancement of ATG5-ATG12 | [ |
H19 | Upregulated | Breast | Paclitaxel | Reducing p-AKT driving apoptotic pathway | [ |
Upregulated | Glioblastoma | Temozolomide | Activating Wnt/β-Catenin pathway | [ |
|
HANR | Upregulated | Liver | Doxorubicin | Binding to GSKIP and decreasing p-GSK2Β thus reducing apoptosis | [ |
HIF1A-AS2 | Upregulated | Bladder | Cisplatin | Increasing HMG1 allows for increased binding to p53, p63, and p73 which decreases apoptosis | [ |
HOTAIR | Upregulated | Breast | Tamoxifen | Binding to ER and activating of GREB1, TFF1, and c-Myc | [ |
Upregulated | Colorectal | Cisplatin | Sponging of miR-203a-3p leads to activation of Β-Catenin/Wnt pathway | [ |
|
Upregulated | Lung | Crizotinib | Inducing of ULK1 phosphorylation leading to autophagy | [ |
|
HOXD-AS1 | Upregulated | Glioblastoma | Cisplatin | Interacting with miR-204 leading to reduction of apoptosis genes caspase-3 and caspase 9 | [ |
Upregulated | Prostate | Paclitaxel; Bicalutamide | Binding to WDR5 causes activation of PLK1, AURKA, FOXM1, CDC25c, UBE2C, CCNA2, and CCNB1 | [ |
|
LBCS | Downregulated | Bladder | Cisplatin and Gemcitabine | Prevents binding to hnRNPK-EZH2 leading to increase in SOX2 thus reducing apoptosis | [ |
LET | Downregulated | Bladder | Gemcitabine | Increase in NF90 leading to suppressing miR-145 | [ |
LINC00460 | Upregulated | Lung | Gefitinib | Acting on miR-769-5p-EGFR axis | [ |
Linc00518 | Upregulated | Prostate | Paclitaxel | Binding to miR-216-5p leads to enhancement of GATA6 | [ |
LUCAT1 | Upregulated | Osteosarcoma | Methotrexate | LUCAT1 3’ UTR region binds to miR-200c preventing competitive inhibition of miR-200c binding to ABCB1 | [ |
MACC1 | Upregulated | Gastric | Oxaliplatin and 5-FU | MACC1 level is dependent upon TGFB1 from mesenchymal stem cells. MACC1 binds to miR-145-5p | [ |
MALAT1 | Upregulated | Colorectal | Oxaliplatin | Binding to miR-218, leading to enhances EZH2 and E-Cadherin | [ |
MBNL1-AS1 | Downregulated | Lung | Gefitinib and Cisplatin | Sponging miR-301b-3p, increasing the levels of TGFBR2 to activated TGF-β | [ |
MEG3 | Downregulated | Lung | Cisplatin | Inactivating of p53 and Bcl-xl, preventing mitochondrial apoptosis | [ |
NEAT1 | Upregulated | Liver | Sorafenib | Suppressing miR-335 causing a decrease in c-MET | [ |
Upregulated | Osteosarcoma | Cisplatin | Knockdown of miR-34-c causing a decrease in cell cycle arrest | [ |
|
Upregulated | Prostate | Docetaxel | Binding to miR-34a leads to enhancement of RET | [ |
|
OIP5-AS1 | Upregulated | Osteosarcoma | Cisplatin | Decrease in miR-34-5p causes elevated levels of LPAAT-Β leading to inactivation of PI3K/AKT/mTOR pathway | [ |
PVT-1 | Upregulated | Colorectal | 5-FU; Cisplatin | Regulating ABCB1, Bcl-2, and mTOR; increase ABCB1, MDPR1 and Bcl-2 but decreasing Bax and cleaved caspase 3 | [ |
Upregulated | Gastric | 5-FU | Increasing Bcl-2 | [ |
|
SBF2 | Upregulated | Glioblastoma | Temozolomide | Sponging miR-151a-3p causing reduction of XRCC4 | [ |
SNHG1 | Upregulated | Liver | Sorafenib | miR-21 enhances SNHG1 causing nuclear retention and upregulation of SLC3A2 and enhancement of AKT pathway | [ |
SNHG12 | Upregulated | Lung | Cisplatin, Paclitaxel, and Gefitinib | Binding directly to miR-181-a causing an increase in phosphorylated MAPK1 which activates MAPK1, MAP2K1, and SLUG pathway thus reducing apoptosis | [ |
TATDN1 | Upregulated | Lung | Cisplatin | Sponging miR-451 leading to enhancement of TRIM66 | [ |
THOR | Upregulated | Gastric | Cisplatin | Binding to 3’UTR of SOX9 leading to SOX9 mRNA stability | [ |
TP73-AS1 | Upregulated | Glioblastoma | Temozolomide | Loss of ALDH1A1 | [ |
TUG1 | Upregulated | Colorectal | Methotrexate | Interacting with miR-186 enhances CPEB2 | [ |
Upregulated | Liver | Adriamycin | Targeting ABCB1, PARP, and caspase-3 | [ |
|
UCA1 | Upregulated | Bladder | Cisplatin | Upregulation of WNT6 pathway | [ |
Upregulated | Breast | Tamoxifen | Activating Wnt/β-Catenin; p-AKT/mTOR | [ |
|
Upregulated | Colorectal | 5-FU | Sponging of miR-204-5p leading to upregulation of Bcl-2, RAB22A, and CREB1 | [ |
|
Upregulated | Lung | Gefitinib | Inducing AKT/mTOR pathway | [ |
|
Upregulated | Prostate | Docetaxel | Reducing miR-204 which increased SIRT1 | [ |
|
XIST | Upregulated | Colorectal | Doxorubicin | Binding to miR-124 leading to an increase in SGK1 | [ |
ZFAS1 | Upregulated | Gastric | cis-platinum and Paclitaxel | Enhancing Wnt/β-catenin pathway | [ |
ARSR: Activated in RCC with sunitinib resistance; PTEN: phosphatase and tension homolog; PI3K: phosphoinositide 3-kinase; AKT: protein kinase 3; ATB: activated by TGF-β; ZEB1: Zinc finger E-Box binding homeobox 1; ZNF1: Zinc finger protein 1; BCAR4: breast cancer anti-estrogen resistance 4; ERBB2: Erb-B2 receptor tyrosine kinase 2; ERBB3: Erb-B2 receptor tyrosine kinase 3; CASC2: cancer susceptibility candidate 2; Bax: Bcl-2 associated X; FOXC2-AS1: cancer susceptibility candidate 2; ABCB1: ATP bonding cassette subfamily B member 1; MDPR1: multi drug resistance protein 1; FOXD-AS1: FOXD2 adjacent opposite strand RNA 1; ABCC3: ATP binding cassette subfamily c member 3; GAS5: growth arrest-specific transcript 5; GBCDRlnc1: gallbladder cancer drug resistance-associated lncRNA1; PGK1: phosphoglycerate kinase 1; HANR: HCC associated long non-coding RNA; GSKIP: glycogen synthase Kinase 3 interacting protein; GSK3β: glycogen synthase kinase 3 β; HIF1A-AS2: hypoxia inducible factor 1 alpha-antisense RNA 2; HMG1: high mobility group Box 1; HOTAIR: HOX transcript antisense RNA; ER: estrogen receptor; GREB1: growth regulating estrogen receptor binding 1; TFF1: trefoil factor 1; ULK1: Unc-51 like autophagy activating kinase 1; HOXD-AS1: HOXD cluster antisense RNA 1; PKL1: kinesin-like protein Pkl1; AURKA: Aurora kinase A; FOXM1: Forkhead Box M; CDC25c: cell division cycle 25c; UBE2C: ubiquitin conjugating enzyme E2 C; CCNA2: cyclin A2; CCNB1: cyclin B1; LBCS: low expressed in bladder cancer stem cells; hnRNPK: heterogeneous nuclear ribonucleoprotein K; EZH2: enzyme of zeste 2 polycomb repressor nuclear complex 2 subunit; SOX2: SRY-box2; LET: low expression in tumor; EGFR: epidermal growth factor receptor; GATA6: GATA binding protein 6; LUCAT1: lung cancer associated transcript 1; MACC1: metastasis associated in colon cancer-1; 5-FU: 5-fluorouracil; MALAT1: metastasis associated lung adenocarcinoma transcript 1; MBNL1-AS1: muscleblind-like 1 antisense RNA 1; TGFBR2: transforming growth factor beta receptor 2; TGF-β: transforming growth factor β; MEG3: maternally expressed 3; Bcl-XL: B-cell lymphoma-extra large; NEAT1: nuclear enriched abundant transcript 1; c-MET: MET proto-oncogene; RET: ret proto-oncogene; OIP5-AS1: OIP5 antisense RNA 1; LPAAT-B: lysophosphatidic acid acyltransferase B; AKT: protein kinase 3; mTOR: mammalian TORC1; PVT-1: plasmacytoma variant transcript 1; Bcl-2: B-cell lymphoma 2; SBF2: SBF2 antisense RNA 1; XRCC4: X-ray repair cross complementing 4; SNHG1: small nucleolar RNA host gene 1; SLC3A2: solute carrier family 3 member 2; SNHG12: small nucleolar RNA host gene 12; MAPK1: mitogen-activated protein kinase 1; MAP2K1: mitogen-activated protein kinase kinase 1; SLUG: snail family transcriptional repressor 2; TATDN1: TatD DNase domain containing 1; TRIM66: tripartite motif containing 66; THOR: testis associated oncogenic; SOX9: SRY-Box 9; TP73-AS1: TP73 antisense RNA 1; ALDH1A1: aldehyde dehydrogenase 1 family member A1; TUG1: taurine upregulated gene 1; CPEB2: cytoplasmic polyadenylation element binding protein 2; PARP: poly ADP ribose polymerase; UCA1: urothelial cancer associated 1; WNT6: Wnt family member 6; RAB22A: RAB22A, Member RAS Oncogene Family; CREB1: CAMP responsive element binding protein 1; SPRK1: SRSF protein kinase 1; SIRT1: NAD-dependent deacetylase sirtuin-1; XIST: X-inactive specific transcript; SGK1: Serum/Glucocorticoid Regulated Kinase 1; ZFAS1: ZNFX1 Antisense RNA 1
A mainstay treatment for a majority of malignancies is chemotherapy. Chemotherapy causes cancer cell toxicity by disrupting DNA replication, which can lead to cell death. There are several classes of chemotherapeutic agents: alkylating agents, platinum complexes, taxanes, tubulin interactive agents, topoisomerase II inhibitors, and anthracyclines[
Alkylating agents principal role is to control DNA synthesis in cells which are undergoing proliferation and in turn causing cytotoxicity. Alkylating agents can affect DNA synthesis by adding an alkyl group to guanine bases of DNA thus inhibiting double helix to properly form[
There have been several lncRNAs that dysregulate glioblastoma’s sensitivity to TMZ. One being lncRNA-TP73-AS1; clinical data has correlated elevated levels of TP73-AS1 to poor prognosis for glioblastoma patients. Analysis looking into glioblastoma cancer stem cells (gCSC) determined TP73-AS1 is higher in gCSC than compared to primary glioblastoma tissue. In addition knockdown of TP73-AS1 in gCSC suppresses cancer stem cell marker ALDH1A1[
LncRNA-SBF2 antisense RNA1 (SBF2-AS1) is located within the exosome of glioblastoma tumor microenvironments and is another regulator of glioblastoma sensitivity to TMZ. SBF2-AS1 is seen to be upregulated in TMZ-resistant glioblastoma cells compared to parental cells. Functional studies found that knockdown of SBF2-AS1 in glioblastoma cells leads to diminished resistance to TMZ[
Platinum based drugs are complexes consisting of neutral platinum (II) with amine ligands. Examples of platinum based drugs on the market are cisplatin, carboplatin, and oxaliplatin[
Cisplatin is a platinum-based chemotherapeutic drug used to treat NSCLC[
The most common subtype of NSCLC is lung adenocarcinoma[
While targeting lncRNAs within NSCLC would be beneficial in enhancing NSCLC sensitivity to therapeutic treatments, the targeting of lncRNAs specific to NSCLC cancer stem cells (CSC) would further increase the efficacy of these drugs. When comparing lncRNAs differentially expressed in NSCLC cells compared to NSCLC CSCs, Li
The multi-modal treatment for muscle-invasive bladder cancer treatment consist of surgery, neoadjuvant chemotherapy-cisplatin, and adjuvant platinum-based chemotherapy[
As with other cancer types, bladder cancer is susceptible to molecular changes based upon oxygen intake and onset of hypoxia. It was found that hypoxic cells have an increase of hypoxia inducible factor 1 (HIF1), leading to elevated levels of lncRNA-hypoxia inducible factor 1α-antisense (HIF1A-AS2), which enhances cisplatin resistance[
While the before mentioned lncRNAs were oncogenic, there are lncRNAs which possess tumor suppressor functions. LncRNA-low expressed in Bladder cancer stem cells (LBCS) was identified through stem cell profiling[
LncRNA-PVT-1 has also been assessed as a regulator of chemoresistance in colorectal cancer by impacting the sensitivity of colorectal cancer cells to cisplatin[
Even with the use of surgery and chemotherapy, the overall survival of patients with advanced gastric cancer is approximately one year[
A tumor suppressive lncRNA, lncRNA-CASC2 was shown to be at lower levels in gastric cancer compared to normal adjacent tissue with additional finding that cisplatin-resistant gastric cells, BGC823 and SGC7901, have decreased levels of CASC2 compared to non-resistant cells. Kaplan-Meier survival analysis also showed a significant correlation between patients with low levels of CASC2 with poor prognosis[
In osteosarcoma, lncRNA-NEAT1 is a regulator of cisplatin sensitivity. With data showing NEAT1 is overexpressed in osteosarcoma tissue in comparison to non-malignant tissues. NEAT1 causes its tumorigenic effect by enhancing osteosarcoma cell viability when treated with cisplatin. Results of both
While in glioblastoma, lncRNA-HOXD-AS1 is a factor that impacts cisplatin induced cell toxicity[
Oxaliplatin, is another platinum based drug[
The presence of mesenchymal stem cells (MSC) in the heterogeneous cellular structure of a tumor is a factor that enhances multi-drug resistance in gastric cancer[
Taxane class of anticancer agents alters the metaphase to anaphase transition by disrupting spindle microtubule formation, thus leading to cell death. Previous literature has cited that taxane resistance can occur in tumors which contain α and Β-tubulin which polymerize into mitrotubules preventing the cell death induced by taxanes[
Triple Negative Breast Cancer (TNBC)/basal-like sub-type makes up 15%-20% of all breast cancer diagnose[
LncRNA-SNHG12 not only regulates NSCLC resistance to cisplatin but also to paclitaxel. NSCLC cells resistant to paclitaxel have higher levels of SNHG12 than non-resistant cells and knockdown of SNHG12 in paclitaxel-resistant lines causes a suppression of paclitaxel resistance. SNHG12 decreases sensitivity through the binding of miR-181-a leading to phosphorylation of MAPK1 thus a reduction in apoptosis[
In gastric cancer, lncRNA-ZFAS1 regulates gastric cancer sensitivity to paclitaxel[
Castration resistant prostate cancer is treated with several taxane-based therapeutics[
LncRNA-NEAT1 is a critical component of the nuclear paraspeckle structure and is elevated levels in prostate cancer tissue and has the ability to enhance tumorigenic behaviors which includes decreasing tumor sensitivity to taxane based chemotherapeutic agent docetaxel[
Doxorubicin is a chemotherapeutic agent used to treat both adult and pediatric cancer. Cell toxicity caused by doxorubicin is through intercalation of DNA and inhibition of topoisomerase II-mediated DNA repair. Doxorubicin resistance has been reported through the activation of resistance-mediated genes such as ABCB1, ABCC1, and TOP2A[
Gallbladder cancer is the fifth most-prevalent digestive malignancy and one reason for poor survival is late detection of malignancy[
Doxorubicin is also used in the treatment of colorectal cancer. Zhu
Adriamycin (doxorubicin) is a chemotherapeutic agent used to treat hepatocellular carcinoma. While chemotherapy is the first-line treatment for hepatocellular carcinoma, there is the possibility of chemotherapeutic resistance[
One lncRNA recently found to be a regulator of doxorubicin sensitivity in osteosarcoma is lncRNA- FOXC2-AS1. FOXC2-AS1 is an antisense lncRNA found to be transcribed from the negative strand of the forkhead box protein C2[
Another chemotherapeutic drug is gemcitabine[
Another lncRNA examined in bladder cancer stem cells is lncRNA-LET. LET is a downstream target of TGFΒ1 and has been shown to be downregulated in bladder cancer cells[
5-Flurouracil (5-FU) is the third most common chemotherapeutic agent used for the treatment of cancer[
Gastric cancer responds to 5-FU in about 30% of cases[
In colorectal cancer, the elevated level of PVT-1 causes inhibition of colorectal cancer cells sensitivity to 5-FU. Fan
Sorafenib is chemotherapeutic agent which inhibits cancer by inhibiting several tyrosine kinases including VEGFR1, c-Kit, and different isoforms of Raf kinase[
Targeted therapy aims to deliver drugs specific to intracellular molecular perturbations or alteration within the tumor microenvironment. The purpose is to reduce the off-target effects which develop when treating cancer patients with other types of therapeutics. As with other cancer therapies, therapeutic resistance is an obstacle when treating patients with targeted agents[
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, with a 5-year survival of about 15%[
Besides its ability to contribute to resistance to cisplatin and paclitaxel, lncRNA-SNHG12 is also able to contribute to NSCLC resistance to gefitinib. The knockdown of SNHG12 enhances NSCLC cells sensitivity to gefitinib through the previously mentioned miR-181/MAPK1 axis[
Human epidermal growth factor receptor 2 (HER2+) breast cancer is the second most lethal subtype of breast cancer[
A therapeutic drug used to treat late-stage NSCLC is crizotinib[
Methotrexate is an inhibitor of dihydrofolate reductase enzyme, an enzyme critical for DNA synthesis and cell growth[
LncRNA-LUCAT1 is seen to be upregulated in methotrexate-resistant osteosarcoma cells compared to methotrexate-sensitive cells. The transient knockdown of LUCAT1 caused an increase in methotrexate sensitivity and also a decrease in the protein level of drug resistance related genes (ABCB1, MRP5, and MVP). Mechanistically, LUCAT1 is able to enhance chemoresistance through LUCAT1 3’ UTR region sponging miR-200c and increasing the expression of ABCB1, which is a known miR-200c target[
Hormone therapy is commonly used to treat both breast and prostate cancer. For breast and prostate cancer, the malignancy is dependent upon the level of steroid hormone receptors. Factors contributing to hormone therapy resistance are pre-receptor level, perturbation of hormone and receptor level, and/or post-receptor level[
Approximately 70% of breast cancer patients have luminal A/estrogen receptor-positive (ER+) breast cancer which consists of low proliferation rate genes such as Ki67 and low levels of HER2[
In non-castration resistant prostate cancer, patients receive androgen therapy, bicalutamide. Bicalutamide are anti-androgen agents that prevents androgen-androgen receptor binding. A common cause of resistance to bicalutamide is development of mutations within the androgen receptor thus preventing bicalutamide sensitivity[
Through the use of transcriptomic analysis such as RNA sequencing, it was found that approximately 75% of the human genome is transcribed[
For many malignancies, small molecule therapeutic treatments are the predominant course of therapy[
Schematic of the lncRNAs that contribute to therapeutic resistance in a variety of malignancies. The arrows represents the direction of dysregulation when cancer is in a therapeutic resistant state
Concept: Tsang S, Patel T, Yustein JT
Design: Tsang S, Yustein JT
Wrote (first draft): Tsang S
Reviewed, edited and revised: Tsang S, Patel T, Yustein JT
Not applicable.
This work was supported by Baylor College of Medicine Comprehensive Cancer Training Program (CPRIT RP160283).
All authors declared that there are no conflicts of interest.
Not applicable.
Not applicable.
© The Author(s) 2019.