Role of non-coding RNAs in modulating the response of cancer cells to paclitaxel treatment

Paclitaxel is a chemotherapeutic substance that is administered for treatment of an extensive spectrum of human malignancies. In spite of its potent short-term effects against tumor cells, resistance to paclitaxel occurs in a number of patients precluding its long-term application in these patients. Non-coding RNAs have been shown to influence response of cancer cells to this chemotherapeutic agent via different mechanisms. Mechanistically, these transcripts regulate expression of several genes particularly those being involved in the apoptotic processes. Lots of in vivo and in vitro assays have demonstrated the efficacy of oligonucleotide-mediated microRNAs (miRNA)/ long non-coding RNAs (lncRNA) silencing in enhancement of response of cancer cells to paclitaxel. Therefore, targeted therapies against non-coding RNAs have been suggested as applicable modalities for combatting resistance to this agent. In the present review, we provide a summary of studies which assessed the role of miRNAs and lncRNAs in conferring resistance to paclitaxel.


Introduction
Paclitaxel is a chemotherapeutic agent being used in a wide range of human malignancies [1].This agent has uncommon biochemical properties.Its structure contains a complex diterpene, a taxane ring, a four-membered oxetane ring and an ester side chain at location C-13 [1].The Food and Drug Administration has approved paclitaxel for the treatment of a variety of cancers including ovarian cancer, breast cancer, lung cancer, and Kaposi's sarcoma [2].In addition, it is administered off-label for the treatment of several other cancers [2].Mechanistically, this agent promotes the polymerization of tubulin to stable microtubules, blocking cells in the G2/M stage of the cell cycle and decapitating them from making a normal mitotic apparatus [1].In vitro studies have shown that this agent decreases the crucial amounts of purified tubulin Abbreviations: lncRNA, long non-coding RNAs; miRNAs, microRNAs; APC, adenomatous colon polyposis protein; CK-1, casein kinase-1; 3 ′ UTR, 3 ′ -untranslated region; NSCLC, Non-Small Cell Lung Carcinoma; LC, Lung Cancer; LCSCs, Lung Cancer Stem Cells; OC, Ovarian Cancer; EOC, Epithelial ovarian cancer; CC, Cervical Cancer; EC, Endometrial carcinoma; BCa, Breast Cancer; TNBC, Triple Negative Breast Cancer; MTMECs, Minimally Transformed Mammary Epithelial Breast Cancer Cells; BCSC, Breast Cancer Stem Cells; CRC, Colorectal Cancer; GC, Gastric cancer; HCC, Hepatocellular Carcinoma; PCa, Prostate Cancer; CML, Chronic Myelogenos Leukemia; OS, Osteosarcoma; NPC, Nasopharyngeal carcinoma; BLC, Bladder Cancer; OS, overall survival; DFS, disease-free survival; RFS, relapse-free survival; LAD, Lung Adeno carcinoma; EC, Endometrial Cancer; RCC, Renal Cell Carcinoma; CRISPR, clustered regularly interspaced short palindromic repeats; gRNA or sgRNA, genome-editing strategy includes two components: a guide RNA; Cas protein, CRISPR-associated endonuclease; HGSOC, High-grade serous ovarian cancer; ATC, Anaplastic thyroid carcinoma; RES, recognition of reticuloendothelial system; MTD, maximum tolerated doses; nab, nanoparticle albumin-bound.* Corresponding author.** Corresponding author at: Research Unit of Non-Coding RNAs and Genome Editing in Cancer, Division of Clinical Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria.E-mail addresses: martin.pichler@medunigraz.at (M.Pichler), mohammad_823@yahoo.com(M.Taheri).Upregulation of miR-30a-5p via suppressing the expression level of BCL-2 could promote paclitaxel [30] (continued on next page) S. Ghafouri-Fard et al.
subunits which is required for polymerization into microtubules and enhances the proportion of tubulin subunits that amass.Besides, microtubules polymerized following treatment with paclitaxel are sheltered from the dissociation typically prompted by exposure to cold or calcium ions [3].Paclitaxel induces mitotic arrest via induction of the mitotic checkpoint, the chief cell cycle regulatory system functioning in the course of mitosis to avoid chromosome mis-segregation [2].In fact, this chemotherapeutic agent arrests cells in the mitosis as a result of existence of small quantities of unattached kinetochores [4].The human albumin-stabilized paclitaxel units have a typical size of 130 nm (https://pubchem.ncbi.nlm.nih.gov/compound/Paclitaxel#section=Therapeutic-Uses).In spite of its potent effects against tumoral cells, primary or secondary resistance to paclitaxel occurs in a number of patients precluding its long-term application in these patients.Notably, attainment of resistance to this drug results in the remarkable aggressiveness of cancer cells and poor clinical outcome [5].Several mechanisms contribute in this phenomenon among them are up-regulation of multidrug resistance proteins, molecular alterations in its cellular targets and alterations in the apoptotic pathways and mitosis checkpoint apparatus [6].Up-regulation of the multidrug transporter proteins which construct the efflux pumps increases effluxion of paclitaxel outside the cells, thus obstructing drug retaining.Among these proteins are ABCB1 (MDR1) and ABCC1 (MRP1) [7][8][9].Moreover, point mutation in the β-tubulin coding gene at the site of paclitaxel attachment is another proposed mechanism for resistance to paclitaxel [10].Besides, changes in the expression quantities of tubulin isotypes might affect response to this drug [11].More recently, non-coding RNAs (ncRNAs) have been shown to influence response of cancer cells to paclitaxel [12].Differential expression of these transcripts between paclitaxel-resistant and -sensitive cancer cells has potentiated ncRNAs as possible culprits in the induction of resistance phenotype [12].In the present review, we provide a review of studies which assessed the role of two classes of ncRNAs i.e. microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in conferring resistance to paclitaxel.

miRNAs and response to paclitaxel
These endogenously produced small RNAs have sizes about 22 nucleotides.They can regulate expression of genes at post-transcriptional level through either cleaving target transcripts or suppressing translation of mRNA to proteins [13].The interactions between miRNAs and mRNAs are complex processes since a certain miRNA can alter expression of numerous target transcripts and expression of each mRNA might be controlled by several miRNAs [14].These small-sized molecules regulate cell differentiation, proliferation and apoptotic processes, thus partake in the evolution of human cancers [14].In addition, they can modulate response of cancer cells to the therapeutic options [15].In the following sections, the role of miRNAs in the modulation of response of different cancer types will be discussed.Previous researches have detected that ectopic expression of microRNAs could have an important role in causing paclitaxel sensitivity in various human cancer cells via modulating some targets.Ma et al. have demonstrated that miR-107 could significantly promote paclitaxel sensitivity in breast cancer cells via Wnt/β-catenin cascade by directly targeting the expression levels of TPD52 and cyclin D1 in both mRNA and protein levels.Therefore, this could provide an evidence of modulating paclitaxel effect on breast cancer cells through the role of miR-107 [16].In addition, Liu et al. also in another study have indicated that upregulation of miR-422a could play a remarkable role in reducing the expression level of TGFβ2 via modulating its downstream effectors namely phosphorylated smad 2 and smad3, and thereby could suppress osteosarcoma cell growth and apoptosis as well as paclitaxel and cisplatin resistance in target cells [17].Another research have illustrated that downregulation of miR-140-3p or miR-155-5p via antagomir could suppress the PI3 K-AKT-mTOR signaling pathway activation, thus reducing phosphorylation of Bad, mTOR and Gsk-3β.This could have an effective role in reducing paclitaxel, doxorubicin, and cisplatin resistance in chordoma by directly targeting the expression level of PTEN which could lead to restraining tumor cell survival, invasiveness, EMT and resistance to chemotherapy drug [18].Fig. 1 illustrates the role of miRNAs in modulation of paclitaxel resistance via regulating TGF-β, Smad and Wnt/β-catenin routes.

Lung cancer
Dysregulation of a number of miRNAs have been noted in cell lines or clinical samples of patients with lung cancer.Moreover, functional studies have shown the effects of miRNAs up-or down-regulation in changing the responsiveness of these cells to paclitaxel.For instance, miR-935 silencing has been shown to enhance expression of SOX7 and increase the anticancer impacts of paclitaxel in lung cancer cells.In addition to its direct effects on expression of SOX7, miR-935 increases levels of Bcl-2 and phosphorylated AKT and reduces expression of the apoptotic protein BAX.Thus, miR-935 has been suggested as a predictor of response of lung cancer cells to paclitaxel [19].miR-421 as another up-regulated miRNA in lung cancer cells has been shown to inhibit expression of KEAP1 through direct interaction with its 3 ′ -untranslated region (3 ′ UTR).Oligonucleotide-mediated miR-421 silencing has enhanced ROS levels and response of cancer cells to paclitaxel both in cancer cell lines and in xenograft models.Further investigations revealed β-catenin as the main regulator of miR-421 expression in lung cancer [20].Notably, miRNAs also mediates the drug-sensitizing effects of a number of agents used as herbal medicine.For instance, Curcumin has been shown to enhance the sensitivity of lung cancer cells to   paclitaxel via up-regulation of miR-30c and subsequent down-regulation of MTA1 [21].Table 1 summarizes the results of studies which appraised the role of miRNAs in the modulation of response of lung cancer to paclitaxel.

Female reproductive system
Expression of miR-181a has been shown to be higher in chemoresistant ovarian cancer tissues compared with chemosensitive samples and normal tissue.Forced over-expression of this miRNA in SKOV3 cells has reduced E-cadherin expression and augmented N-cadherin    expression.Such effects have been accompanied by induction of chemoresistance in these cells [33].Another study in ovarian cancer cells revealed down-regulation of the miR-134 gene cluster while up-regulation of the miR-17-92 gene cluster in the paclitaxel-resistant cells compared with sensitive cells.Assessment of the expression of targets of these miRNAs in the mentioned cell lines showed differential expression of these proteins among paclitaxel-resistant and -sensitive cells, further highlighting the role of these miRNA clusters in the modulation of response of ovarian cancer cells to paclitaxel [27].In cervical cancer cells, miR-21 silencing has enhanced cell apoptosis, inhibited cell proliferation, decreased expression of Bcl-2, survivin, c-myc and p-AKT while increased expression of Bax, PDCD4 and PTEN.Moreover, knock down of this miRNA enhanced anticancer effects of paclitaxel in these cells [34].Table 2 summarizes the results of studies which assessed the role of miRNAs in the modulation of response of cancers of female reproductive system to paclitaxel.

Breast cancer
Forced over-expression of miR-520 h in MCF-7 breast cancer cells has enhanced cell proliferation and suppressed paclitaxel-induced cell apoptosis.On the other hand, silencing of miR-520 h promoted the paclitaxel sensitivity in the resistant cells.Mechanistically, this miRNA targets OTUD3 to modulate paclitaxel resistance in these cells.Furthermore, miR-520 h suppresses PTEN expression via OTUD3 and consequently influences function of downstream p-AKT pathway [55].A microarray study has shown down-regulation of miR-155-3p while up-regulation of miR-155-5p in paclitaxel-resistant breast cancer cells compared with parental cells.A 21-residue peptide namely NT21MP has been shown to combat paclitaxel-resistance phenotype of breast cancer cells via targeting miR-155-3p and miR-155-5p through the CXCR4 pathway [56].miR-21-5p is another up-regulated miRNA in paclitaxel resistant breast cancer cell lines.This miRNA has been shown to directly target PDCD4.Knock down of this miRNA reduces paclitaxel resistance and suppresses cancer cell progression via up-regulation of PDCD4 [57].Table 3 shows the role of miRNAs in the modulation of response of breast cancer to paclitaxel.

Gastrointestinal (GI) cancers
Several studies have been shown a disease-modifying and prognosis determining effect and microRNAs in colorectal cancer [88,89].miR-29a has been shown to contribute in both evolution of colorectal cancer and resistance of these cells to chemotherapeutic agent, paclitaxel.This miRNA inhibits expression of PTEN.Expression of this miRNA has been up-regulated paclitaxel resistant colorectal cancer cells.Inhibition of expression of this miRNA leads to over-expression of PTEN, suppression of p-AKT, attenuation of cell proliferation, and enhancement of apoptosis paclitaxel resistant cells [90].Exosomal miR-522 has been shown to inhibit expression of ALOX15, a gene which is implicated in the production of lipid-ROS in gastric cancer.Such exosomes are mainly originated from cancer-associated fibroblasts in tumor microenvironment.Notably, cisplatin and paclitaxel enhance miR-522 secretion from these fibroblasts through stimulating USP7/hnRNPA1 axis, resulting in ALOX15 inhibition, reduction of lipid-ROS buildup and diminished sensitivity to the chemotherapeutic agents [91].miR-16 is another miRNA whose expression has been down-regulated in the hepatocellular carcinoma samples and cell lines.Down-regulation of miR-16 has been shown to confer chemoresistance through modulation of IKBKB and NF-κB signaling pathway [92].Table 4 summarizes the results of studies which assessed the role of miRNAs in the modulation of response of GI cancers to paclitaxel.

Prostate cancer
The anti-cancer flavonoid morin has been shown to suppress the cell viability of paclitaxel-treated prostate cancer cells possibly via downregulation of miR-155.This miRNA has been reported to directly suppress GATA3 expression.Therefore, morin has been suggested as a possible adjuvant of paclitaxel in treatment of prostate cancer which exerts its role via modulating miR-155/GATA3 axis [98].Expression of miR-199a has been decreased in prostate cancer samples, especially recurrent ones.This miRNA has also been suppressed in paclitaxel-resistant cells.Forced up-regulation of this miRNA reverses paclitaxel resistance in these cells via modulating expression of YES1.Therefore, this miRNA has the capacity for combating paclitaxel resistance in prostate cancer [99].Table 5 summarizes the role of miRNAs in the modulation of response of prostate cancer to paclitaxel.

Other cancers
In addition to the mentioned cancer types, miRNAs modulate response of other types of cancers to paclitaxel.For instance, suppression of miR-140-3p or miR-155-5p in chordoma cell has decreased the malignancy of these cells, reduced activity of PI3 K-Akt-mTOR pathway, and enhanced anti-cancer effects of paclitaxel through up-regulation of PTEN protein level [18].Expression of miR-9-3p (miR-9) has been shown to be decreased in adriamycin (ADR)-resistant K562/ADR cells and chronic myeloid leukemia patients with multidrug resistant phenotype.Forced up-regulation of this miRNA could attenuate cancer cell resistance to several chemotherapeutic agents both in vitro and in animal models.This miRNA has been shown to target ABCB1 [102].Table 6 summarizes the results of studies which assessed the role of miRNAs in the modulation of response of other cancers to paclitaxel.

Prognostic value of paclitaxel-associated miRNA in cancers
Consistent with the role of miRNAs in the modulation of response to paclitaxel, these miRNAs can alter patients' outcome.For instance, overexpressions of miR-520 h, miR-522 and miR-421 have been associated with poor outcome of patients with breast cancer, gastric cancer and lung cancer, respectively (Table 7).On the other hand, up-regulations of miR-4282 and miR-137 confer better survival of patients with breast cancer and lung cancer, respectively (Table 7).

LnRNAs and response to paclitaxel
LncRNAs can control important cellular functions via interplay with several types of biomolecules such as proteins, chromatin and RNA.They can interact with the epigenetic apparatus and recruit a number of associated proteins to specific loci, modulating methylation marks of DNA or epigenetic marks of histones.With diverse regulatory roles on gene expression, they contribute in the pathogenesis of several kinds of cancers [106].Moreover, they alter response of cancer cells to   [109].Fig. 2 represents the dysregulation of various types of lncRNAs which negatively modulate expression of target genes through the PI3 K/AKT/mTOR and MAPK/ERK signaling pathways leading to decreasing paclitaxel sensitivity in human cancer cells and causing poor response to treatment.

Lung cancer
KCNQ1OT1 is an up-regulated lncRNA in lung adenocarcinoma tissues and cell line.Notably, over-expression of this lncRNA has been correlated with malignant features of this cancer.Its silencing has suppressed lung cancer cell proliferation and invasion and induced apoptosis in these cells.This lncRNA has higher expression levels paclitaxel resistant patients compared with paclitaxel responsive ones.KCNQ1OT1 silencing also suppressed expression of MDR1 protein in lung cancer cells [110].NEAT1 is another up-regulated lncRNA in paclitaxel-resistant lung cancer cells line.Knockdown of this lncRNA ameliorated the paclitaxel-resistance phenotype via induction of apoptosis through enhancing expression levels of cleaved PARP and cleaved caspase-3.Besides, NEAT1 has a role in activation of the Akt/mTOR pathway through up-regulation of p-Akt, p-mTOR, Bcl-2 and down-regulation of Bax [111].Table 8 summarizes the results of studies which assessed the role of lncRNAs in the modulation of response of lung cancers to paclitaxel.

Female reproductive system
In paclitaxel resistant ovarian cancer cells, NEAT1 has been up-regulated.This lncRNA serves as a molecular sponge for miR-194 to decrease its bioavailability.NEAT1 silencing has reversed paclitaxel resistance and enhanced paclitaxel-induced apoptosis in cell lines and animal models.NEAT1 exerts its effects through up-regulation of ZEB1, the molecular target of miR-194 [114].In cervical cancer samples, over-expression of LINC00511 has been associated with the tumor stage, tumor size and lymph node involvement.Knock down of this lncRNA in cervical cancer cells has led to down-regulation of MRP1, P-GP, Bcl-2, MMP-2 and MMP-9, while up-regulation of Bax and cleaved-caspase-3 levels.Besides, LINC00511 knock down enhanced sensitivity of these cells to paclitaxel and decreased viability, proliferation, migration and invasion of these cells [115].Table 9 summarizes the role of lncRNAs in the modulation of response of cancers of female reproductive system to paclitaxel.

Head and neck cancers
In nasopharyngeal cancers, up-regulation of n375709, CCAT1 and H19 has been associated with paclitaxel resistance [126][127][128].Mechanistically, CCAT1 serves as a molecular sponge for miR-181a.miR-181a has been identified as a regulator of paclitaxel resistance that modulates apoptosis through targeting CPEB2 [126].Table 10 summarizes the results of studies which assessed the role of Role of lncRNAs in the modulation of response of head and neck cancers to paclitaxel.

Breast cancer
The importance of lncRNAs in conferring resistance to paclitaxel has been evaluated in breast cancer cells, principally in triple negative breast cancer (TNBC).For instance, expression of lncRNA H19 has been higher in paclitaxel-resistant compared with paclitaxel-sensitive cell lines.Its silencing has enhanced sensitivity of sensitivity of paclitaxelresistant TNBC cells to this agent through modulating the AKT signaling pathway [107].LINC00511 is another up-regulated lncRNA in breast cancer tissues and cell lines.Notably, up-regulation of this lncRNA has been associated with up-regulation of CDK6, while down-regulation of miR-29c.LINC0051 has direct interaction with miR-29c to decrease its expression.LINC00511 silencing improves sensitivity of breast carcinoma cells to paclitaxel through increasing miR-29c levels and subsequently decreasing CDK6 levels [129].

Sample Number Kaplan-Meier Analysis Multivariate Cox Regression Ref 156 pairs of BCa and ANCs
Higher expression of miR-520 h was associated with poorer OS rate.
Higher expression of miR-520 h was associated with tumor size, histological grade, lymph node metastasis.
[55] 100 pairs of BCa tissues and ANCs Patients with miR-4282 negative expression had lower OS rate.
Lower expression of miR-4282 was associated with tumor stage and tumor metastasis. [62] 43 pairs of CC tissues and ANCs Lower expression of miR-125a was associated with poorer OS rate.
Lower expression of miR-125a was associated with poorer FIGO stage and tumor size. [52] 45 pairs of GC tissues and ANCs and plasma samples Higher expression of miR-522 was associated with poorer OS rate.
- [91] 50 pairs of NSCLC tissues and ANCs Lower expression of miR-137 was associated with poorer OS and DFS rates.
- [26] 266 pairs of NSCLC tissues and ANCs Patients with higher expression of miR-186 had better OS rate.
Lower expression of miR-186 was associated with lymph node metastasis and tumor stage. [29] 94 pairs of NSCLC tissues and ANCs Lower expression of miR-30a was associated with poorer OS and DFS rates.
- [30] 10 NSCLC serum samples and 10 nontumor serum specimens Higher expression of miR-421 was associated with poorer OS rate.
Higher expression of miR-421 was associated with smoking history, tumor stage, and pathological patterns. [20] 48 pairs of OC tissues and ANCs Higher expression of circTNPO3 was associated with poorer OS rate.
Higher expression of circTNPO3 was associated with FIGO stage and histological type. [40] 44 pairs of OC tissues and ANCs Lower expression of miR-136 was associated with poorer OS rate. - TCGA database Lower expression of miR-34a was associated with poorer OS rate.
42 pairs of TNBC tissues and ANCs Lower expression of miR-335 was associated with poorer OS rate. - S. Ghafouri-Fard et al.Table 11 summarizes the results of studies that assessed the role of lncRNAs in the modulation of response of breast cancer to paclitaxel.

GI cancers
Expression levels of lncRNAs can also modulate response of colorectal cancer, gastric cancer and liver cancer cells to paclitaxel.In gastric cancer, HOTAIR up-regulation has been associated with paclitaxel and doxorubicin resistance.This lncRNA has been up-regulated in gastric cancer tissues particularly those obtained from advanced stages.Forced over-expression of HOTAIR has augmented cell proliferation, promoted cell cycle progression, enhanced migration and confers resistance to paclitaxel via suppressing miR-217 expression and increasing expression levels of GPC5 and PTPN14 [137].The role of this lncRNA in enhancing chemoresistance in hepatocellular carcinoma is exerted through interaction with miR-34a [138].Table 12 summarizes the role of lncRNAs in the modulation of response of GI cancers to paclitaxel.

Prostate cancers
DANCR has been shown to target and miR-135a and suppress its expression in prostate cancer cells.miR-135a is a tumor suppressor miRNA that inhibits cell proliferation, enhances cell apoptosis and promotes paclitaxel sensitivity in these cells.Therefore, DANCR silencing represents a novel strategy for increasing paclitaxel sensitivity in prostate cancer cells [140].Linc00518 is another up-regulated lncRNA in prostate cancer.Over-expression of this lncRNA has been linked with paclitaxel resistance.Linc00518 acts as a molecular sponge for miR-216b-5p to inhibit its expression [141].Table 13 summarizes the role of lncRNAs in the modulation of response of prostate cancer to paclitaxel.

Other cancers
MA-linc1 is an lncRNA whose suppression affects cell cycle distribution, resulting in a reduction in the quantities of G1 cells and a simultaneous upsurge in all other stages of the cell cycle, particularly G2/M.Therefore, this lncRNA is involved in the regulation of M phase.MA-linc1 silencing suppresses M phase exit due to the induction of freedom from a mitotic block.MA-linc1 mainly acts in cis to suppress transcription of its adjacent gene, Purα.Suppression of MA-linc1 increases paclitaxel-associated cell apoptosis through modulation of Purα.Over-expression of MA-linc1 has eben associated with poor clinical outcome in breast and lung cancer patients [142].Table 14 summarizes the results of studies which assessed the role of lncRNAs in the modulation of response of other cancers to paclitaxel.

Prognostic value of paclitaxel-associated miRNA in cancers
Expression levels of several lncRNAs that modulate response of cancer cells to paclitaxel have been associated with clinical outcome of cancer patients.For instance, over-expressions of ANRIL, HOTAIR, TUG1, LINC00511 and LINC00160 confer poor overall survival in different cancer types.On the other hand, down-regulations of ENST00000500843, ADAMTS9-AS2 and TCL6 were associated with poor clinical outcome of patients (Table 15).

Designing CRISPR/Cas9 System to overcome resistance to paclitaxel
Clinical evidence demonstrated that paclitaxel resistance is a main hurdle in the treatment of different types of human cancers which causes the disease out of control and leads to high mortality [145][146][147].Tumor cells attain resistance to multiple chemotherapeutic agents after repeated remedies, which is a serious obstacle to attain efficient cancer therapy.Multiple mechanisms are involved in the development of paclitaxel resistance.These mechanisms include DNA repair cascades mutation, ectopic expression of miRNAs, aberrant expression of long non-coding RNAs, resistance to the starting of the apoptotic cascade, and the promotion of ceaselessly activated signaling pathways, and transforming drug metabolism [148][149][150][151][152]. For instance, ectopic expression of NF-κB1, c-Rel, and ELK1 could lead to TAB1 upregulation that in turn play an important role in downregulating and/or inhibiting the expression level of miR-134 and confer resistance of serous epithelial ovarian cancer cells to paclitaxel [153].It is remarkably practical to modulate the genome with the clustered regularly interspaced short palindromic repeats (CRISPR)/associated (Cas) 9 technology.Being currently developed, it might play an important role in enhancing paclitaxel sensitivity in cancer cells [154][155][156].The conventional mechanism to reduce attained drug resistance is to synthesize agents by adding to different targets.These approaches of sensitizing tumor cells interact with each other, and the efficacy can be difficult to predict.

Table 8
Role of lncRNAs in the modulation of response of lung cancers to paclitaxel (ANCs: adjacent normal controls).[109] S. Ghafouri-Fard et al.

Table 9
Role of lncRNAs in the modulation of response of cancers of female reproductive system to paclitaxel (ANCs: adjacent normal controls).Application of CRISPR/Cas9 system presents an effective procedure for development of novel model systems for the targeted alteration of endogenous loci, and this cutting-edge genome-editing tool can be altered to permit creation of more alterations to adjust gene expression beyond simple gene knockdown.Related methods are gene manipulation to suppress chemoresistance drugs, screening, recognition of different resistance molecular targets, and altering membrane transport proteins to enhancing drug delivery [21,[157][158][159].The main dysregulation of signaling cascades in paclitaxel resistance is related to Wnt/β-catenin, PI3 K/AKT/mTOR, HER2, HER3, MAPK/ERK, NF-κB, TGF-β, and PTEN/AKT pathways [16,18,75,148,[160][161][162][163].In order to figure out the efficacy of miR-195 expression on the response of NSCLC cells to MTAs in paclitaxel resistance, Ye et al. knocked out miR-195 utilizing CRISPR/Cas9 with pair of sgRNAs designed against the miR-195 locus.Therefore, by applying this gene-editing tool, they discovered that miR-195 with paclitaxel and eribulin could suppress the expression level of CHEK1, and thereby blocking the growth of cancer cells in NSCLC and contributing to sensitize to MTAs [28].In addition, another research demonstrated ectopic expression for miR-421 results in paclitaxel resistance in NSCLC.In order to identify the upstream regulator of miR-421, one of the targets gene, β-catenin, was knocked out through the CRISPR/Cas9 procedure in NSCLC cells.Blocking the expression of miR-421 via AMO could promote ROS levels and the expression level of KEAP1, and thereby enhancing paclitaxel sensitivity in NSCLC and reducing cell proliferation, invasion, and migration significantly [20].Therefore, the CRISPR/Cas9 system has been offered as a remedial method to reduce drug resistance in different paclitaxel-resistant cancers.This engineered genome-editing strategy includes two components: a guide RNA (gRNA or sgRNA) and a CRISPR-associated endonuclease (Cas protein).The gRNA is a short synthetic RNA produced of a scaffold sequence essential for Cas-binding and a user-defined ~20 nucleotide spacer that facilitates the genomic target to be altered [164,165].Cas9-mediated HDR could create an accurate recombination event between a homologous DNA donor template and the impaired DNA region, leading to a precise modification of the double-strand breakage.Thus, HDR can be applied to offer specific correction or transgenes into the genome [166,167].In order to eliminate the effect of antigen-specific T-cells directed against Cas9 protein and suppress the immune reaction with the aim of enhancing the chance of appropriate delivery of the CRISPR-Cas9 system, exosome-mimetic nanoplatforms, lipopolymer or viral vectors can be used to encapsulate this gene-editing tool that can promote the sensitivity of tumor cells to chemotherapy [168][169][170][171]. Therefore, the CRISPR/Cas9 system is a innovative gene editing method that can revert drug resistance due to secondary genomic mutations to a minimal level in resistance to anti-cancer drugs with an exact sgRNAs design and effective delivery.Fig. 3 depicts knocking out of tak1 gene through CRISPR/Cas9 system in order to improve paclitaxel sensitivity in tumor cells that can lead to decreasing phospho-JNK and PARP cleavage levels, and thereby triggering cell death via the activation of TAK1-JNK signaling pathway [172].Additionally, a summary of clinical researches in order to detect the role of various genes causing paclitaxel resistance in different human cancer cells via CRISPR/Cas9 system is demonstrated in Table 16.

Paclitaxel nano-delivery systems leading towards promoting therapeutic applications in different human cancers
Nanoparticle delivery systems has recently drawn attention, particularly with the aim of improving patient outcomes in various types of cancer remedies.As an efficient chemotherapeutic factor, via encapsulating paclitaxel in different nano-delivery systems it can play an important role in promoting the standard-of-care remedy in variety of cancer cells [191,192].One of the significant factor due to enhancing paclitaxel efficiency by packaging via nano-delivery systems based on polymers or lipids can increase the aqueous solubility of this drug remarkably and as a consequence elevate response to treatment.In addition, another valuable characteristic of these delivery systems that can take into consideration is their small size leading to promoting permeability and retention (EPR) effect of molecules of certain sizes typically liposomes, and nanoparticles in targeting cells.Importantly, this type of encapsulating paclitaxel can provide an opportunity to not be recognized via the recognition of reticuloendothelial system (RES) which can attenuate the side effects of our target drug in non-cancerous tissues.Therefore, higher maximum tolerated doses (MTD) of nanoparticles has become possible.High stability, high carrier capacity can also be considered as another significant technological advantages of these nanoparticles.[193][194][195].Schmid et al. have detected that atezolizumab-nab-paclitaxel in patients with PD-L1-positive tumors in  triple-negative breast cancer accompanied with the desirable level of immunotherapy effectiveness among patients in both the intention-to-treat population and the PD-L1-positive subgroup.Therefore, nanoparticle albumin-bound (nab)-paclitaxel can plan an effective role in anticancer activity of chemotherapeutic drugs [196].Another research have noted that, paclitaxel-loaded PBCA nanoparticles could eliminate multidrug resistance and promote the level of cytotoxicity to a large extent in ovarian cancer cells via suppressing P-gp activity creating through the nanoparticles system.Therefore, it can provide a promising mechanism to enhance nanoparticles efficacy and make them applicable procedure to lead drug delivery [197].In addition, Zou et al. have demonstrated that a dual-drugs co-delivery nano-sized system contained by the dendrimer-derivative PEG-PAMAM copolymer with PTX and BNL co-loaded could be considered as an effective method to restrain multiple drug resistance in ovarian cancer cells which in turn could lead to more cytotoxicity and apoptosis, and increasing tumor cell growth suppression.As a consequence, PEG-PAMAM NPs could provide evidence of attenuating MDR in tumor cells after exposure to a chemotherapeutic agent including paclitaxel and Borneol and improving therapeutic efficacy as well [198].Another study have discovered that multiblock HPMA copolymer-GEM and HPMA copolymer-PTX conjugates by transferring them as a combination of single factors that can provide a helpful procedure in order to remedy ovarian cancer [199].
Yin et al. have illustrated that R8-dGR peptide modified PTX and HCQ   S. Ghafouri-Fard et al.
their particular morphology can have a helpful role in diminishing the limitations caused by paclitaxel containing excessive drug accumulation, uncontrolled drug release, tumor cells resistance to chemotherapeutic drugs and improvement of drug-loading capacity with the aim of enhancing response to therapy in glioma patients [202].An Overview of various paclitaxel loaded polymeric and lipid-based nanoparticles is represented in Table 17.

Discussion
Paclitaxel is an extensively used chemotherapeutic agent in the treatment of human cancers.Emergence of resistance to this drug is regarded as a major problem in the clinical settings.Dysregulation of ncRNAs has been shown to be implicated in this problem.Consistent with the widespread use of paclitaxel in the treatment of patients with ovarian, breast or lung cancers, these types of cancers have been the mostly assessed malignancies in the terms of assessment of the role of ncRNAs in conferring resistance to paclitaxel.Wnt/β-catenin, AKT/ERK, PI3 K/AKT, mTOR, NF-κB and STAT related pathways are among the pathways which are involved in the process of modulation of paclitaxel sensitivity by ncRNAs.In addition, a number of paclitaxel-sensitizing herbal agents exert their effects through modulation of expression of ncRNAs.Therefore, ncRNAs are regarded as molecular targets for enhancement of the effects of herbal medicines as well.
The significant role of ncRNAs in conferring paclitaxel resistance/ sensitivity has also been reflected by their remarkable impact on clinical outcome of patients with diverse types of cancers.As a rule, overexpression of miRNA/lncRNAs that enhance sensitivity of cancer cells to this drug is associated with higher survival of patients and vice versa.

Conclusion
LncRNAs and miRNAs interact with each other to modulate response of cancer cells to paclitaxel.Several lncRNA/miRNA axes have been identified to be functional in this regard.For instance, the SNHG5/ miR-23a and NEAT1/miR-194 axes in the ovarian cancer [35,114] and Linc00518/ miR-216b-5p axis in the prostate cancer [235] are among functional axes in the regulation of response of cancer cells to paclitaxel.These observations further highlight the importance of comprehensive assessment of expression pattern of different classes of ncRNAs for clarification of the molecular pathways in this cellular process.
Based on the remarkable roles of ncRNAs in altering response of cancer cells to paclitaxel, targeted therapies against these transcripts represent a putative treatment modality for combating resistance to this agent and enhancing survival of patients.The results of in vivo studies support the applicability of antisense oligodeoxyribonucleotide therapies in animal models.However, these modalities have not been examined in the clinical settings.

Fig. 1 .
Fig. 1.A schematic representation of the TGF-β, Smad and Wnt/β-catenin signaling pathway causing paclitaxel resistance in cancer cells via dysregulation of miRNAs.β-catenin can interact with GSK3β, axin2, APC, and CK-1.Through binding with FZD and LRP5/6 coreceptor complex, Wnt can inhibit β-catenin phosphorylation and its transfer to the nucleus.In nucleus, β-catenin can bind to TCF/LEF transcription factors in order to enhance expression of targets such as cyclin D1, c-myc, or c-jun.Some studies have demonstrtaed the effect of Wnt/β-catenin and TGF-β expression in inducing drug resistance in various human cancer cells.The abnormal expression of miRNAs could negatively regulate Wnt, GSK3β, β-catenin, and TGF-βII which can play a crucial role in chemotherapy resistance especially reducing the effect of paclitaxel in target cancer cells.miR-152 induces activation of PKM2, cell proliferation, and tumorigenesis as well as paclitaxel resistance.

Fig. 2 .
Fig. 2. A schematic illustration of lncRNAs in modulation of ensitivity of human cancer cells to paclitaxel via the PI3 K/AKT/mTOR and MAPK/ERK signaling pathways.Ectopic expression of lncRNAs could significantly reduce the phosphorylation of PI3 K, AKT and mTOR, indicating the role of these lncRNAs in the modulation of paclitaxel resistance through suppressing the PI3 K/AKT/mTOR pathway.Alteration of the mitochondrial apoptotic pathway including BCL-2, BCL-xL, Mcl-1, and Bax can also be associated with paclitaxel resistance in various cancer cells via aberrant expression of some lncRNAs.Besides, some lncRNAs can affect phosphorylated MEK1/2 and ERK1/2 and induce resistance to paclitaxel through MAPK/ERK pathway.Furthermore, triggering EMT via the abnormal expression of lncRNAs could be associated with upregulation of N-cadherin followed by the overexpression of vimentin and downregulation of E-cadherin, and thereby enhancing metastasis, tumorigenesis, and resistance to paclitaxel in target cells.

Fig. 3 .
Fig. 3.A schematic diagram of tak1eCRISPR plasmid combined with PTX with the aim of editing TAK1 gene to attenuate paclitaxel resistance via the TAK1-JNK signaling pathway.TAK1 and TAB1 can have effective roles in triggering apoptotic process via NF-κB, JNK, ERK, and p38 signaling transduction cascades.Upregulation of TAK1 in tumor cells treated with CRISPR editing of the tak1 gene mutation accompanied with paclitaxel treatment could provide a remarkable evidence of enhancing cell death rate, PARP cleavage and phosphorylation of JNK.This cutting-edge gene editing tool via inserting a cytosine base and creating frameshift mutation in TAK1 gene could trigger cell apoptosis through the TAK1-JNK activation pathway, and thereby enhancing paclitaxel sensitivity in cancer cells.As a consequence, this can highlight the role of TAK1 gene in chemosensitivity of paclitaxel and other chemotherapeutic agents.

Table 1
Role of miRNAs in the modulation of response of lung cancer to paclitaxel (ANCs: adjacent normal controls).

Table 2
Role of miRNAs in the modulation of response of cancers of female reproductive system to paclitaxel (ANCs: adjacent normal controls).

Table 3
Role of miRNAs in the modulation of response of breast cancer to paclitaxel (ANCs: adjacent normal controls).

Table 3
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Table 3
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Table 4
Role of miRNAs in the modulation of response of GI cancers to paclitaxel (ANCs: adjacent normal controls).
chemotherapeutic agents such as paclitaxel.In the following sections, we describe the role of lncRNAs in the modulation of response of cancer cells to this drug.Previous studies have demonstrated that the remarkable role of dysregulated lncRNAs in causing tumor cell growth, tumor metastasis as well as chemotherapy resistance.Han et al. have indicated that downregulation of lncRNA H19 could play an important role in promoting sensitivity to paclitaxel in TNBC cells by directly modulating AKT signaling pathway and overexpression of apoptotic regulatory

Table 6
Role of miRNAs in the modulation of response of other cancers to paclitaxel.

Table 5
Role of miRNAs in the modulation of response of prostate cancer to paclitaxel.
[108]ins like Bax, Bcl-XL, and Bcl-2.As a consequence it can lead to triggering apoptosis in target cells[107].Another research have illustrated that downregulation of lncRNA SNHG6 could elevate the expression level of miR-186 and thus reducing paclitaxel resistance in prostate cancer cells as well as tumor cell proliferation and invasion.In addition the knockout of SNHG6 could lead to inhibiting the expression levels of Vimentin, CyclinD1, MMP9, Snail, and ZEB1 and promoting the level of E-cadherin in PCa cells chemotherapy resistance[108].

Table 10
Role of lncRNAs in the modulation of response of head and neck cancers to paclitaxel.

Table 11
[201]of lncRNAs in the modulation of response of breast cancer to paclitaxel (ANCs: adjacent normal controls).-loadedliposomescouldbereally beneficial in accumulating chemotherapeutic drugs in tumor cells providing antimetastatic activity with suppression of tumor cell proliferation in primary and metastatic melanoma both in vivo and in vitro[200].Furthermore, in another research Zhong et al. have detected that PTX nanodrug co-administered with iRGD can be taken into account as an effective drug delivery candidate for the treatment of colorectal cancer by increasing the facilitation of tumor penetration, and promoting tumor accumulation and antitumor effects[201].Additionally, another research discovered that by applying implantable rough PTX-PLGA-MS microspheres because of co

Table 12
Role of lncRNAs in the modulation of response of GI cancers to paclitaxel (ANCs: adjacent normal controls).

Table 13
Role of lncRNAs in the modulation of response of prostate cancer to paclitaxel (ANCs: adjacent normal controls).

Table 14
Role of lncRNAs in the modulation of response of other cancers to paclitaxel (ANCs: adjacent normal controls).

Table 16
Pre-clinical researches applying CRISPR/Cas9 to detect the role of various genes in response to chemotherapeutic options.

Table 17
An overview of PX-loaded Polymeric and Lipid nanoparticles.
(continued on next page) S.Ghafouri-Fard et al.