Exosome and miRNA Regulation in Drug Resistance

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1		Mariaconcetta Cariello	--	2411	2023-01-06 17:03:02	\|
2	format correct	Catherine Yang	-1 word(s)	2410	2023-01-09 02:08:58	\|

This entry is adapted from the peer-reviewed paper 10.3390/molecules28010116

Extracellular vesicles (EVs), including exosomes, have an important role thanks to their ability to communicate and exchange information between tumor cells and the tumor microenvironment (TME), and have also been associated with communicating anti-cancer drug resistance (DR). The increase in proliferation of cancer cells alters oxygen levels, which causes hypoxia and results in a release of exosomes by the cancer cells. miRNAs play a fundamental role, as they can activate changes in gene expression. Additionally, a growing number of studies have associated microRNAs to DR, demonstrating their regulatory role even in the therapy response of hematological tumors.

drug resistance tumor microenvironment hypoxia exosomes miRNAs

1. Exosomal miRNA: Biogenesis

miRNAs are a class of small non-coding RNAs, typically 19–25 nucleotides long, which mediate post-transcriptional gene silencing by binding to the 3′-UTR region or to the Open Reading Frame of the target mRNA ^[1]. Therefore, miRNAs have not only the remarkable ability to regulate different biological processes—such as proliferation, angiogenesis, and metastasis—by altering gene expression, but also to remodel the TME in order to signal to the immune system ^[2]. It is also known that changes in the expression of miRNAs, during chemotherapy treatments, have been proposed as a tool to monitor the efficacy of the therapy and the risk of relapse ^[3]. At the same time, the TME modulates the expression of miRNAs by releasing SF (cytokines and growth factors) by both the tumor and non-tumor cells, or by the presence of mechanisms such as hypoxia, starvation, and pH alterations, as described above. A sequence of two 4-nucleotide sequences, recognized by the RNA binding protein Heterogeneous Nuclear Ribonucleoproteins A2/B1 (hnRNPA2B1), is used for the sorting of miRNAs in exosomes, as indicated by data in the literature. A study by Wang et al. has shown that, in hypoxic conditions of the TME, exosomes relate to transformation of the tumor phenotype by the transfer of miR-193-3p, miR-210-3p, and miR-510-5p ^[4] and are capable of activating the transition between epithelium and mesenchyme—one of the mechanisms used for DR ^[5]. In Table 1 , the miRNAs and the pathway that will be discussed in the following paragraph.

Table 1. Principal miRNAs involved in drug resistance (DR) of hematological tumor.

Hematological Tumor	miRNA	Drug Resistance	Cell Type	Pathway	Ref.
Chronic myeloid leukemia (CML)	miR-1228 miR-1246 miR-1308 miR-149 miR-455-3p miR-365 miR-27a miR-451 miR-21	Imatinib Imatinib Imatinib Imatinib Imatinib Imatinib Resistance phenotype Resistance phenotype Resistance phenotype	CEM CEM CEM CEM CEM CML CML CML CML	Exosome increaseExosome increase Exosome increase Exosome increase Exosome increase Bax-Caspase3 P-gp P-gp P-gp	^[6] ^[6] ^[6] ^[6] ^[6] ^[7] ^[8] ^[8] ^[8]
Acute myeloid leukemia (AML)	miR-7977 miR-19b miR-20a	Anthracyclines Anthracyclines Anthracyclines	HL-60/AR HL-60/AR HL-60/AR	P-gp PTEN and P-gp PTEN and P-gp	^[9] ^[10] ^[10]
Chronic lymphocytic leukemia (CLL)	miR-146a	Resistance phenotype	CCL	Akt-NF-kB	^[10]
Lymphoma	miR-181a miR-548m miR-99a-5p miR-125b-5p	Resistance phenotype Resistance phenotype Resistance phenotype Resistance phenotype	NHL NHL DLBCL DLBCL	Bim c-Myc-HDAC6 Exosome increase Exosome increase	^[11] ^[12] ^[13] ^[13]
Multiple myeloma	miR-627-3p miR-642a-5p miR-16-5p miR-15a-5p miR-20a-5p miR17-5 miR-30	Bortezomib Bortezomib Bortezomib Bortezomib Bortezomib Bortezomib Resistance phenotype	LP-1 myeloma cells LP-1 myeloma cells U-226 myeloma cell U-226 myeloma cell U-226 myeloma cell U-226 myeloma cell H929 myeloma cell	SP9-PI3K/Akt SP9-PI3K/Akt Exosome increase Exosome increase Exosome increase Exosome increase BCL9-Wnt	^[14] ^[14] ^[15] ^[15] ^[15] ^[15] ^[16]

2. Exosomal miRNA: Mechanism and Action in Solid Tumor

Exosomes released by drug resistant cancer cells typically have a different cargo than exosomes released by sensitive cancer cells, hereby mediating the horizontal transfer of DR traits from drug-resistant cancer cells to drug-sensitive ones. The different exosomal miRNAs exert their role in DR through the following mechanisms: I) by alteration of the drug efflux pump, II) increased resistance to apoptotic stimuli, and III) modulation of the tumor microenvironment ^[17]^[18].

2.1. Alteration of Drug Efflux Pump

Many studies suggested that exosome secretion acts as a signal to change the sensitivity of tumors to chemotherapy drugs and tumor progression. Meanwhile, exosomes can expel a variety of compound drugs out of tumor cells, reduce tumor cells’ DR, and thus lead to the failure of chemotherapy ^[19]. Levchenko and colleagues demonstrated that the expression of exosomal protein P-gp is regulated by miR-451 and miR-27a. They can maintain a prolonged expression of the P-gp proteins, with consequent upregulation, which contributes to the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). These cells are known to be involved in DR mechanisms ^[4], through the alteration of drug efflux pumps ^[20]. In fact, P-gp, the most important drug transporter, can induce an acquired resistance phenotype associated with miRNAs, through blocking apoptosis by increasing the expression of the MDR1 gene, which encodes P-gp ^[21].

2.2. Increased Resistance to Apoptotic Stimuli

Overall, miR-21 is a key regulator of the oncogenic processes that promote cell survival, and the formation and activation of CAFs ^[1] by regulating TGFβ1 signaling ^[22]. Isolated exosomes derived from hepatocellular carcinoma (HCC) patients can convert normal hepatic stellate cells to CAFs via miR-21, which downregulates the phosphatase and tensin homolog (PTEN) tumor suppressor gene, and consequently upregulates the PI3K/Akt signaling pathway ^[23]. The Yan-Ran group has instead shown that miR-21, released from gastric tumor cells, promotes resistance to apoptosis through the PTEN/PI3K/Akt pathway; it is known for its role in the regulation of various biological processes such as transcription, protein synthesis, metabolism, autophagy, proliferation, apoptosis, angiogenesis, and migration ^[24]. The regulation of miRNAs involves a loss of function of PTEN, which acts as a gatekeeper of the pathway, with a consequent increase in the invasion capacity and aggressiveness of the tumor. On the other hand, a gain of function of PI3K and Akt promotes survival and anti-apoptotic mechanisms ^[25]. miR-21, released from exosomes derived from cells resistant to cisplatin, induces resistance to sensitive cells by acting on the pathway of phosphatases and the homolog of tensin (PTEN) to regulate the mechanism of programmed cell death ^[26]. Fu et al. demonstrated that MDR liver cells transfer miR-32-5p to sensitive cells by exosomes, which in turn activates the PI3K pathway through the Akt pathway, capable of inducing resistance ^[27].

2.3. Modulation of the Tumor Microenvironment

This bidirectional communication between the tumor cells and the fibroblasts reprogrammed in CAFs, through the exosomes, allows for the creation of an optimal microenvironment for tumor growth, giving a more aggressive phenotype to tumor cells; thus, allowing them to adapt to the “new” microenvironment ^[28]. A further study showed that miR-222, released from exosomes in lung cancer cells, is correlated with a high tumor aggressiveness, as these miRNAs act on the downregulation of the target gene PDLIM2, which in turn activates the nuclear factor NF-kB ^[29]. Further studies have been carried out on miR-1246, which is highly present in solid tumors, and is found in the microenvironment and released by exosomes. The overexpression of Caveolin 1 (Cav1), the direct target of miR-1246, sensitizes cells to paclitaxel, by reducing the levels of the p-gp protein (MDR1) ^[30]. Furthermore, a study using exosomal human melanoma miRNAs showed that miR-155 and miR-210 induce metabolic changes in adult human fibroblasts to increase aerobic glycolysis, promoting a pre-metastatic microenvironment ^[31]. In particular, miR-155 and miR-210 are referred to as oncogenic miRNAs that drive resistance to therapy in different types of cancer ^[32]^[33]^[34]. While cancer-derived exosomal miRNAs can promote CAFs differentiation, CAFs-released exosomal miRNAs in the TME play an important role in therapy resistance. Next-generation sequencing technology demonstrated that exosomal transfer of miR-21, from CAFs to ovarian cancer cells, inhibited apoptosis and promoted resistance to treatment with different types of drugs. ^[1]

3. Exosomal miRNA in Hematological Tumor

miRNAs can be transferred from tumor cells to adjacent cells in their cell-free circulating exosome ^[35]. miRNA expression has been widely associated with different diseases, including several cancers such as hematological malignancies, through the targeting of mRNAs coding for proteins influencing drug-resistance (such as drug efflux pumps, increased resistance to apoptotic stimuli, and modulation of the tumor microenvironment) ^[36]. Table 2 summarizes the principal action type of exosomes and related miRNA, with their specific mechanisms.

Table 2. Principal type of action of exosomes and related miRNAs with their specific mechanism.

Type of Action	Name	Mechanism	Ref.
Exosome increase	miR-1228, miR-1246, miR-1308, miR-149, miR-455-3p	More abundant in the exosomes of ALL cell line	^[6]
	miR-99a-5p, miR-125b-5p	Higher in exosomes from serum of chemo-resistant patients	^[13]
Drug resistance	miR-365	Inhibiting expression of pro-apoptosis proteins BAX and Cleaved Caspase-3 in CML cells	^[7]
	miR-27a, miR-451, miR-21	Increasing expression of P-gp	^[8]
	miR-7977	Increasing expression of P-gp	^[9]
	miR-19b, miR-20a	Targeting PTEN and decreasing activation of PI3K/Akt signaling pathway	^[10]
	miR-146a	Activating Akt pathway and NF-kB in CLL	^[10]
	miR-181a	Protecting lymphoma cells from drug-induced apoptosis through BIM	^[11]
	miR-548m	Promoting c-Myc activation in lymphoma cells	^[12]
	miR-627-3p, miR-642a-5p	Targeting SP9 and activation of PI3K-Akt signaling pathway	^[14]
	miR-30	Enhancing expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway	^[16]
Exosomal biomarker	miR-15a-5p, miR-20a-5p, miR-17-5, miR-16-5p	Downregulation in exosomes from patients resistant to Btz compared to patients sensitive to Btz	^[15]

3.1. miRNA and Leukemia: Chronic Myeloid Leukemia (CML)

In CML, the majority of patients can be treated with TKIs, such as IM, but some patients will develop DR. Studies have identified exosomes as promoters of DR in cancer ^[37]. Jaiswal et al. demonstrated that several miRNAs (miR-1228*, miR-1246, miR-1308, miR-149*, miR-455-3p) were more abundant in the exosomes of the ALL cell line CCRF-CEM (designated CEM for simplicity), compared to healthy donor cells. The same miRNAs were found to be significantly increased in drug-sensitive cells upon co-culturing with drug-resistant exosomes ^[6], confirming the role of exosomes in tumor progression. Min et al. demonstrated that IM-sensitive CML cells exhibited DR after having been incubated with exosomes derived from IM-resistant CML cells. They identified a differential miRNA expression profile in exosomes, deriving from either IM-resistant or IM-sensitive CML cells. Moreover, they observed the highest miR-365 expression level in exosomes of IM-sensitive CML cells, and identified that exosomes mediated the transfer of miR-365 between IM resistant and sensitive CML cells, and that miR-365 induced DR by inhibiting expression of pro-apoptosis proteins BAX and Cleaved Caspase-3 in IM-sensitive CML cells ^[7]. Additionally, another study confirmed that the transfer between resistant and sensitive CML cells of the drug resistant phenotype is mediated through exosomes ^[8]. Exosomes deriving from resistant cells, containing miR-27a, miR-451, and miR-21, have been shown to be related to P-gp expression and can also contribute to chemotherapy resistance in tumor cells. Another study suggests that exosomes released by IM-resistant CML cells (K562/G01) were internalized by sensitive CML cells (K562), thus horizontally transferring miR-365 that confers DR to the recipient cells ^[7].

Acute Myeloid Leukemia (AML)

The upregulation of miR-7977 in AML exosomes was found to have a role in the disruption of normal hematopoiesis, and in the aberrant production of hematopoietic growth factors ^[9]. P-gp can be expressed on cancer cells of AML patients and contributes to resistance to anthracyclines in vitro. The study of Bouvy demonstrated that exosomes from the drug-resistant HL-60 cell line (HL-60/AR) can interact with their sensitive (HL-60) counterpart cells and enable resistant cells to transfer their drug-resistance phenotype to sensitive cells ^[10]. In particular, two miRNAs, miR-19b and miR-20a, were found to be more expressed (> 4-fold change) in exosomes of sensitive cells as compared to resistant cells. These increased P-gp expression, targeted PTEN, and decreased the activation of the PI3K/Akt signaling pathway; this signaling pathway is often constitutively activated in AML ^[10].

Chronic Lymphocytic Leukemia (CLL)

CLL-derived exosomes have been demonstrated to deliver miRNAs to stromal cells that acquired features of cancer-associated fibroblasts, promoting CLL progression. In particular, miR-146a was specifically enriched in CLL exosomes as compared to a healthy subject’s cells (ratio 15:1) and was able to induce activation of the Akt pathway and NF-kB ^[10].

3.2. Exosomal miRNA and Lymphoma

Follicular dendritic cells (FDCs) are stromal cells that support lymphoma progression, and their adhesion to NHL cells is associated with DR ^[11]. Lwin et al. showed that NHL cell adhesion to FDC induced the upregulation of miR-181a, through B-cell lymphoma-2 (BCL-2)–interacting mediator of cell death (BIM) downregulation and, consequently, protected lymphoma cells from drug-induced apoptosis ^[11]. The same group discovered that miR-548m downregulation, and subsequent histone deacetylase 6 (HDAC6) overexpression, enhances the adhesion of NHL to lymphoma stroma cells, promoting sustained c-Myc activation. Interestingly, c-Myc is a target of miR-548m, forming an amplification loop in these cancers. Both mechanisms, regulated by the tumor microenvironment, suggest that alterations in specific miRNA levels lead to DR and lymphoma survival ^[12]. Additionally, in NHL and diffuse large B-cell lymphoma (DLBCL), miR-99a-5p and miR-125b-5p were found significantly upregulated in exosomes from resistant cells, when compared to sensitive parental cells’ exosomes ^[13]. The expression levels of miR-99a-5p and miR-125b-5p were higher in exosomes from the serum of chemo-resistant DLBCL patients, as compared to the sensitive ones, thus being associated with a worse prognosis ^[13]. Additionally, it has been suggested that exosomal miRNAs could be used as predictive biomarkers of chemotherapeutic efficacy in DLBCL patients ^[13].

3.3. Exosomal miRNA and Multiple Myeloma (MM)

Thanks to the novel therapy for MM patients using Btz, panobinostat, melphalan, and lenalidomide, the survival rate of these patients has significantly improved in the past years. The interaction between myeloma cells and the BMME plays a pivotal role in MM initiation, progression, and DR. BMME-derived exosomes antagonize Btz-induced apoptosis and decrease the viability of MM cells ^[14]. Tang and co. employed KEGG analysis on Btz-resistant MM cells and found four enriched terms associated with DR, including the mechanistic target of rapamycin (mTOR), and the cAMP and PI3K–Akt signaling pathways. Moreover, bone marrow stromal cell derived exosomes (BMSC) influence multiple signal transduction pathways, such as JNK and p38 MAP kinases (MAPK), p53, and Akt, that affect the survival of MM cells, thus stimulating MM-cell growth and inducing Btz resistance ^[14]. Their results also indicate that miR-627-3p and miR-642a-5p target the transcriptional factor SP9, and that these miRNAs may bind differentially expressed exosomal lncRNA involved in PI3K-Akt signaling pathways ^[14]. Zhang et al. analyzed the cargo of exosomes from the plasma of MM patients treated with Btz and identified several miRNAs ^[15]. Specifically, they found exosomes with significantly increased internal RNAs and a downregulation of miR16-5p, miR-15a-5p, miR-20a-5p, and miR-17-5 in exosomes from patients resistant to Btz, as compared to patients sensitive to Btz. This suggests the use of exosomal miRNAs as DR biomarkers for MM ^[15]. Moreover, Zhao et al., knowing of the correlation between miR-30 and B-cell lymphoma 9 (BCL9), observed another correlation between MM cell lines and cells from MM patients. In fact, H929 cells (MM cell lines) co-cultured with BMSCs showed miR-30 downregulation, associated with an enhanced expression of BCL9, which is a transcriptional coactivator of the Wnt signaling pathway, known to promote multiple myeloma cell proliferation and DR ^[16].

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Mariaconcetta Cariello

Angela Squilla

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Giorgia Venutolo

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Update Date: 09 Jan 2023

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