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Chakrabortty, A.; Patton, D.J.; Smith, B.F.; Agarwal, P. miRNAs in Cancer Treatment. Encyclopedia. Available online: https://encyclopedia.pub/entry/46531 (accessed on 22 June 2024).
Chakrabortty A, Patton DJ, Smith BF, Agarwal P. miRNAs in Cancer Treatment. Encyclopedia. Available at: https://encyclopedia.pub/entry/46531. Accessed June 22, 2024.
Chakrabortty, Atonu, Daniel J. Patton, Bruce F. Smith, Payal Agarwal. "miRNAs in Cancer Treatment" Encyclopedia, https://encyclopedia.pub/entry/46531 (accessed June 22, 2024).
Chakrabortty, A., Patton, D.J., Smith, B.F., & Agarwal, P. (2023, July 06). miRNAs in Cancer Treatment. In Encyclopedia. https://encyclopedia.pub/entry/46531
Chakrabortty, Atonu, et al. "miRNAs in Cancer Treatment." Encyclopedia. Web. 06 July, 2023.
miRNAs in Cancer Treatment
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MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that regulate gene expression post-transcriptionally by binding to messenger RNAs. miRNAs are important regulators of gene expression, and their dysregulation is implicated in many human and canine diseases. Most cancers tested to date have been shown to express altered miRNA levels, which indicates their potential importance in the oncogenic process.

miRNAs cancer oncomiRs tumor-suppressor miRNAs

1. Introduction

miRNAs are small non-coding RNA sequences with an average length of 18–22 bps. To date, 2654 mature miRNAs have been reported in humans [1]. miRNAs play an essential role in biological processes by regulating gene expression at the post-transcription level. miRNAs bind to messenger RNA (mRNA) in the cytoplasm, resulting in mRNA degradation or temporary inhibition of translation until needed [2]. Downregulation of a specific miRNA leads to upregulation of the corresponding proteins’ expression and vice-versa. Conversely, upregulation of miRNA leads to decreased target protein(s) expression. miRNAs bind at the 3′ and 5′ untranslated regions (UTRs) and coding regions of mRNA to induce translation repression. miRNAs are also involved in inducing gene transcription by binding within the promoter regions of a gene [3]. miRNAs are typically found inside cells; however, a portion of them are shed into circulation in lipid-coated particles known as exosomes [4]. Circulatory exosomal miRNAs have been identified as possible disease biomarkers as they are stable in blood and are protected from endogenous RNAse activity [5].
miRNAs play an important role in cancer cell transformation. miRNAs can function as tumor-suppressor genes or oncogenes by targeting genes involved in tumor development and progression or cell-cycle inhibition, respectively. Since the discovery of microRNAs, they have held great promise for cancer diagnosis, prognosis, and therapy. Different miRNA profiles can be identified for different tumor types, which could then serve as phenotypic signatures for exploitation in cancer diagnosis, prognosis, and treatment. If miRNA profiles can accurately predict malignancies, this technology could be used as a tool to overcome many diagnostic challenges [6].

2. Role of miRNAs in Cancer

2.1. Humans

2.1.1. OncomiRs

OncomiRs are defined as miRNAs that are overexpressed in tumors, repress tumor-suppressor mRNAs, and stimulate tumor cell proliferation and metastasis (Figure 1) [7]. There are many different oncomiRNAs with different roles in cancer growth that have been identified so far.
Figure 1. miRNAs can be classified as oncomiRs and tumor suppressors. (A) OncomiRs suppress tumor-suppressor gene translation and promote tumor cell growth through constitutive overexpression. (B) Tumor-suppressor miRNAs inhibit tumorigenesis and subsequent cancer development by suppressing the translation of mRNAs that encode for oncogenes. (C) Hallmarks of carcinogenesis. This figure was created using Biorender.
The miR-17-92 cluster (miRs-17, -18a, -19a, -20a, -19b, and -92a) downregulates PTEN (phosphate and tensin homolog), E2F, the transforming growth factor-β (TGF-β) signaling pathway, B cell lymphoma/leukemia 2-like protein 11 (BCL2L11), and thrombospondin-1 (TSP-1) [8]. Functionally, it favors tumor growth and is reported to be overexpressed in small-cell lung cancer, colon cancer, hepatocellular carcinoma, thyroid cancer, colorectal adenoma organoids, and renal cell carcinoma [9][10][11][12][13][14].
miR-21 is associated with phosphatase and tensin homolog (PTEN), Tropomyosin 1 (TPM1), and programmed cell death 4 (PDCD4) downregulation. miR21 overexpression is reported in a variety of cancers, such as breast, ovarian, colon, etc. [15][16][17]. Elevated levels of miR-21 were also reported in the serum, plasma, and tumor tissues in breast, lung, ovarian, colon, prostate, pancreatic, and gastric cancer patients [18][19][20][21][22][23][24][25][26][27]. Downregulation of miR-21 reduces cancer proliferation and reverses drug resistance in pancreatic, ovarian, and breast cancers [25][26][27].
miR-181 is an oncomiR that is also upregulated in various cancer types [28]. miR-181a-5p promotes breast tumor progression through N-Myc downstream-regulated gene 2 (NDRG2)-induced activation of the PTEN/AKT signaling pathway and inhibition of sprouty RTK signaling antagonist 4 (SPRY4), PH domain, leucine-rich repeat protein phosphatase 2 (PHLPP2), and inositol polyphosphate 4-phosphatase type II (INPP4B) [29][30][31]. miR-181 facilitates prostate cancer cell proliferation by targeting dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X, gene 1 (DAX-1) [32]. Similarly, miR-181 upregulation is associated with poor prognosis and survival in oral squamous cell carcinoma and drug resistance in melanoma [33]. miR-146a is significantly higher in plasma samples from breast cancer patients [34]. miR-221/222 is overexpressed in liver tumorigenesis and breast, colon, and pancreatic tumors [22][35][36][37].

2.1.2. Tumor-Suppressor miRNAs (TS-miRNAs)

Ts-miRNSa are defined as miRNAs that downregulate cancer progression (Figure 1). The downregulation of tumor-suppressor miRNAs plays a crucial role in cancer development and proliferation [38]. TS-miRNAs are more susceptible to mutations due to their location in cancer-associated genomic regions or fragile sites. Downregulation of TS-miRNAs may occur due to dysfunctional proteins involved in their biogenesis or due to any genetic alteration [39]. Inhibition of the expression of important miRNA biogenesis machineries, such as Drosha, DiGeorge Critical Region 8 (DCGR8), and Dicer, substantially decreases miRNA production and promotes a more transformed cell phenotype [40][41][42][43][44][45].
Loss of TS-miRNA miR-16 is correlated with the progression and expansion of chronic lymphocytic leukemia, gastric, prostate, and pancreatic tumors [46][47][48][49][50]. Let-7 family miRNAs are tumor suppressors that target the Rasa and Myc oncogenes [51]. Ectopic expression of the Let-7 miRNA family induces cell death in lung cancer cells [52]. The Let-7 miRNA family is also reported to target other oncogenes, such as high-mobility group A2 (HMGA2) and MYCN [53]. The Let-7 miRNA family also acts as a tumor suppressor in breast cancer by inhibiting ERα-mediated cellular malignant growth [54].
miR-29 and miR-34 are tumor-suppressor miRNAs whose downregulated expression is associated with the progression and invasion of breast cancer, lung cancer, neuroblastoma and glioblastoma, colon cancer, stomach cancer, osteoblastoma, ovarian cancer, bladder cancer, cervical cancer, cholangiocarcinoma, melanoma, and prostate cancer [55][56][57][58][59]. miR-29 downregulation is also associated with cisplatin resistance in ovarian cancer and elevated cell proliferation in osteosarcoma [60][61][62]. Downregulation of miR-34 is associated with proliferation in pancreatic cancer, lung squamous cell carcinoma, head and neck cancer, colorectal cancer, gastric cancer, and epithelial ovarian cancer [63][64][65][66][67][68]. Elevated expression of miR-362-3p interrupts the cell cycle and inhibits tumor growth, resulting in an improved prognosis in colorectal carcinoma patients [69].
Upregulated miR-193b expression results in reduced fatty acid synthase (FASN), which in turn makes triple-negative breast cancer cells more sensitive to the effects of metformin [70]. The expression of miRNA-193b acts as a tumor suppressor in pancreatic cancer and is markedly reduced in tissues with advanced neoplasia. Cell lines transfected with miRNA-193b exhibited significantly decreased proliferation, migration, and invasiveness [71].
The impact of miRNA polymorphisms and their associated impact on cancer risk have been studied [72][73]. Single-nucleotide polymorphisms (SNPs) rs3746444 in miR-499 and rs4919510 in miR-608 are significantly associated with an increased risk of lung cancer [74]. An SNP in miRNA-499 increases the risk of prostate cancer [72]. X-inactivation-specific transcript (XIST) is a carcinogenic long coding RNA involved in ovarian tumor progression by regulating miR-355/BCL2L2 [75].

2.2. Dogs

Dogs have high similarity to humans in gene sequence and gene function. Dogs share the same environmental exposures and risks as humans. Almost 50% of dogs, 10 years old or older, are diagnosed with cancer at some point in their lives [76]. Due to these similarities, dogs are excellent translational models for complex human diseases, such as cancer. As in humans, miRNAs play an important role in canine cancer.
Upregulation of miRNA-19a, -19b, -17, -5p were reported in T and B cell lymphomas in dogs [77]. Additionally, miRNA-203, -181a, and -218 were reported to be underexpressed in canine lymphoma cell lines and tissues [77]. miRNA-9 enhances mast cell tumor progression [78]. miRNA-145, -203, and -205 are downregulated in canine melanoma [79][80]. miRNA-123b is significantly overexpressed in B cell chronic lymphocytic leukemia (CLL). miRNA-155 is preferentially overexpressed in T lymphocytes and some B cell CLLs, and miRNA-150 is overexpressed in T cell CLL in comparison to B cell CLL [81]. miRNA-214 promotes apoptosis in hemangiosarcoma, and miRNA dysregulation is also involved in canine splenic hemangiosarcoma [82][83]. miRNA expression profiles differ in canine splenic hemangiosarcoma, nodular hyperplasia, and normal spleens. A total of 22 miRNAs were differentially expressed in canine hemangiosarcoma samples compared to normal spleen and nodular hyperplasia [82].
In canine mammary tumors (CMTs), expression of mi-RNA-141 showed post-transcriptional downregulation of the tumor-suppressor gene family INK4A/CDKN2A [84]. miRNA-21 and -29b were reported to be upregulated in mammary gland tumor tissues, and miR-141 was reported to be overexpressed in canine mammary tumor cell lines, whereas miRNA-31, -34a, and -143/145 were reported to be downregulated in canine mammary tissues [84]. Similar miRNA expression is reported in human and dog mammary tumor patients. miR-15a and miR-16 are downregulated in canine ductal carcinomas, while miR-181b, miR-21, miR-29b, and miRlet-7f are upregulated in tubular papillary carcinomas [85]. miR-29b, miR-101, miR-143, and miR-145 expression levels were downregulated and miR-125a expression levels are upregulated in canine mammary tumors compared to normal mammary cells [86].

3. Role of miRNAs in Cancer Treatment

3.1. Humans

As stated above, each cancer possesses a specific combination of miRNAs, either overexpressed oncomiRNAs targeting tumor-suppressor genes or downregulated tumor-suppressor miRNAs targeting oncogenes [87]. This profile of expressed miRNAs may be used to establish a “fingerprint” that could potentially identify specific tumor types and even subtypes with a given tumor. Since miRNAs are involved in cancer cell gene regulation, these may provide excellent opportunities to design personalized therapeutics for cancer patients. miRNA-based anti-cancer therapies have recently generated interest either as monotherapies or in combination with other cancer therapies. Targeting oncomiRNAs induces the expression of tumor-suppressor genes, which in turn enhance tumor cell killing and promote tumor regression [88]. However, physiological and cellular barriers hamper the in vivo efficacy of anti-miRNA technologies.
As previously mentioned, one of the first miRNAs detected in the human genome, miR-21, is overexpressed in glioblastoma [89] and could be used as a therapeutic target in this type of cancer. In glioblastoma cells, the additive interaction of antisense oligonucleotide inhibitors to both miRNA-21 and miRNA-10b may constitute an effective therapeutic strategy to control glioblastoma growth by inhibiting oncogene expression and inducing tumor-suppressor gene expression. miRNA-21 inhibitors also interrupt the activity of the EGFR pathway, thereby increasing the expression of PDCD4 and Tropomyosin 1 (TPM1) and reducing the activities of matrix metalloproteinases (MMPs) [89]. Inhibition of NADPH oxidase (NOX) dramatically lowered the invasive potential of lung cancer in vitro by decreasing miRNA-21-expression [90].
When miRNA inhibitors are co-administered with an anti-cancer agent, they can induce synergistic effects (e.g., in glioblastoma) [91]. A concern in miRNA modulation strategies is the proper identification, in silico, of miRNA inhibitors or analogs that can effectively inhibit or mimic the function of specific miRNAs to achieve miRNA loss or gain of function, respectively. Another challenge to miRNA-directed therapies’ efficiency is the long-term release of these miRNA inhibitors or mimics at their specific target sites. A new form of miRNA inhibitor delivery has been developed to answer these concerns, specifically targeting miRNA-155 in an acidic tumor microenvironment in murine lymphoma. To achieve this, peptide nucleic acid anti-miRs were attached to a peptide with a low pH-induced transmembrane structure (pHLIP). This construct could target the tumor microenvironment and transport anti-miRs under acidic conditions across the plasma membrane. This approach evades the hepatic barrier (removal of foreign proteins from circulation by the hepatic reticuloendothelial system) and facilitates miRNA targeting through a non-specific endocytic pathway [92]. An alternative miRNA inhibitor delivery strategy using R3V6 peptide was evaluated as a transporter of antisense oligodeoxynucleotides [93]. Serum stability assays showed that R3V6 protected miRNA inhibitors from nucleases more efficiently than polyethyleneimine (PEI; 25 kDa, PEI25k). In an in vitro transfection assay, R3V6 transported antisense oligodeoxynucleotide anti-miRNA-21 into cells more efficiently than PEI (25 kDa, PEI25k) and lipofectamine [93].
microRNA can also serve as a candidate for developing oncolytic virotherapy. A new miRNA-modified Coxsackievirus B3 (CVB3) was developed by inserting miR-145/143, miR-1, and miR-216 target sequences into the 5′ untranslated region (5′ UTR) of the CVB3 genome. miR-145/143 is downregulated in tumors, miR-1is muscle-specific, and miR-216 is pancreas-selective [94]. The virus is downregulated in any cell expressing any of the three miRNAs but is replication-competent in cells, such as a tumor, that do not express any of the three. This novel miRNA-modified oncolytic virus inhibited triple-negative breast cancer growth in immunocompromised mouse models [94].
Chemotherapy and miRNA therapy combinations have shown synergistically increased antineoplastic activities. The combination of a miRNA-21 inhibitor and Taxol is an effective therapeutic strategy to control the growth of glioblastoma multiforme (GBM) by inhibiting the expression and phosphorylation of STAT3 in vitro [95].

3.2. Dogs

Canine hemangiosarcoma has an extremely poor prognosis. Upregulation of miR-214 induces apoptosis in hemangiosarcoma cell lines. Intraperitoneal administration of synthetic miR-214 (miR-214/5AE) exhibits anti-tumor effects in a murine model of canine hemangiosarcoma. It induces apoptosis and prohibits cell proliferation [96]. Similarly, intratumoral administration of synthetic miRNA-205 (miR-205BP/S3) can be used to treat canine malignant melanoma. Administration of miR-205BP/S3 in eleven dogs led to five complete remissions, three dogs with stable diseases, and three cases of progressive disease [97].
Novel miRNA vectors are being explored to induce oncolysis and disease remission in solid tumors leading to a new wave of cancer treatments [98]. Canine osteosarcoma patients with metastatic disease have poor prognosis. miR-34a suppresses the oncogene Eag-1, and the downregulation of miR-34a has been correlated with the progression of canine osteosarcoma. In vitro and in vivo models showed that administration of miR-34a inhibited osteosarcoma progression and decreased Eag-1 production [99]. A bioengineered miRNA prodrug (tRNA/miR-34a) was successfully processed into mature miR-34a in canine osteosarcoma cells. The administration of tRNA/miR-34a in murine models with canine OSA xenografts caused delayed tumor growth, increased necrosis and apoptosis, and reduced cellular proliferation [98]. tRNA/miR-34a treatment showed 32% less tumor growth and more prolonged survival versus the control groups [98]. The emergence of new research on the effects of miRNA on tumor progression allows for novel treatment development.

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