The emerging role of miRNAs in combined cancer therapy

Abstract

MicroRNAs (miRNAs) control physiological and fundamental processes in cellular development and differentiation by modulating the expression of their target genes. They have been found to participate in cell transformation and multiplication by functioning as oncomiRs and tumor suppressors in diverse cancers. Introduction of antisense miRNAs (antagomiRs) into primary cells such as immune cells by lipofection, viral vectors or electroporation can achieve the specific silencing of individual miRNAs. Therefore, harnessing miRNAs may lead to promising cancer therapeutics. There is emerging evidence demonstrating the involvement of miRNAs in combined cancer therapies, including chemotherapy, radiotherapy and immunotherapy combining with miRNA therapy.

Keywords:

• chemotherapy
• combined cancer therapy
• immunotherapy
• microRNA
• radiotherapy

1. Introduction

MicroRNAs (miRNAs) are regulators of tumorigenesis and cancer metastasis through the inhibition of gene expression. Therefore, there is an increasing interest in developing anticancer therapies using miRNAs [1]. Indeed, the ability of miRNA to target multiple genes in the context of network pathways strengthens miRNA-based therapies for biological regulatory processes in association with pathological cell homeostasis.

2. miRNA modulation combined with conventional treatments as a novel therapeutic strategy for cancer

He et al. [2] demonstrated that targeting miR-21 could enhance the effects of chemotherapeutic drugs. He showed that miR-21 suppression in combination with 5-fluorouracil and pirarubicin treatment inhibited tumor growth in a subcutaneous xenograft hepatocellular carcinoma mouse model. Combining miR-21 with chemotherapy may be a novel approach for the treatment of hepatocellular carcinoma. Another oncomiR, miR-155, was also found to be a chemotherapeutic target in glioblastoma. Knockdown of miR-155 sensitized glioma cells to temozolomide by targeting the p38 isoforms mitogen-activated protein kinase 13 (MAPK13) and MAPK14 [3].

MUC13, a transmembrane mucin, is highly involved in pancreatic cancer progression. Khan et al. [4] demonstrated that miR-145 targeted the 3′ untranslated region of MUC13 and downregulated MUC13 protein expression in cells. Transfection with miR-145 inhibited cell proliferation, invasion and enhanced gemcitabine sensitivity, leading to a reduction of HER2, P-AKT and PAK1 expression and an increase in p53 expression. In addition, Kim et al. [5] prepared an adenoviral constructed miR-145 (Ad-miR-145) and found that Ad-miR-145 suppressed cell growth and motility in both breast cancer cells in vitro and an orthotopic mouse breast cancer model in vivo. Treatment combining Ad-miR-145 with 5-fluorouracil significantly improved the antitumor effects compared with 5-fluorouracil treatment alone.

Mucositis in the form of ulceration in the oral cavity during chemotherapy and ionizing radiation is a known toxicity risk. Oral mucositis alters gene expression patterns in epithelial tissues that are governed by a number of factors, including transcription factors, RNA-binding proteins and miRNAs [6]. Radiotherapy is an essential primary treatment for cancer patients, although tumor radioresistance and recurrence are common. Wang et al. [7] discovered that miR-24 inhibited the cell growth of human nasopharyngeal carcinoma (NPC) by acting as a radiosensitizer in NPC cells when used in a combined therapy with irradiation. miR-185-3p [8] and miR-205 [9] also affected the radioresistance of human NPC by directly targeting WNT2B and PTEN, respectively. Yuan et al. [10] demonstrated that upregulated miR-218 was able to resensitize human cervical cancer cells to radiation by promoting cellular apoptosis.

Radiotherapy causes the release of tumor antigens in the tumor microenvironment, which may enhance the effects of immunotherapy. The fine-tuning of gene expression by miRNAs that takes place in various immune cells as part of both the innate and cell-mediated responses in the immune system denotes the involvement of miRNAs in antitumor immunity [11]. NK cells are innate immune cells that can eliminate cancer cells and some viral infections. Yun et al. [12] suggested that miR-583 could act as a negative regulator of NK cell differentiation by silencing IL-2Rγ expression, a suggestion that adds to our understanding of the application of human NK cells in immunotherapy. By contrast, CD8⁺ cytotoxic T lymphocytes have potent antitumor activity and have been used for adoptive cell transfer cancer immunotherapy. Lin et al. [13] reported that the functional blocking of miR-23a in human cytotoxic T lymphocytes could enhance granzyme B expression with upregulated BLIMP-1, which might hinder tumor progression. Table 1 summarizes the miRNAs and their actions in combination with conventional therapeutic strategies.

Table 1. Therapeutic strategies in combination with miRNAs.

Therapeutic strategy	Type of cancer	miRNAs in combination	Actions by miRNAs	mRNAs involved	Ref.
Chemotherapy	Hepatocellular carcinoma	miR-21	Inhibiting tumor cell growth		[2]
	Glioblastoma	miR-155	Knockdown of oncomiR miR-155 sensitizing glioma cells to temozolomide	MAPK13, MAPK14	[3]
	Pancreatic cancer	miR-145	Transfection of miR-145 inhibiting cancer cell proliferation and enhancing gemcitabine sensitivity	MUC13	[4]
	Breast cancer	miR-145	Adenoviral constructed miR-145 suppressing growth of breast cancer cells		[5]
Radiotherapy	NPC	miR-24	Acting as a radiosensitizer in NPC cells		[7]
		miR-185-3p	Affecting the radioresistance of human NPC	WNT2B	[8]
		miR-205	Affecting the radioresistance of human NPC	PTEN	[9]
	Cervical cancer	miR-218	Resensitizing cervical cancer cells to radiation		[10]
Immunotherapy	Antitumor immunity	miR-583	Acting as a negative regulator of NK cell differentiation	IL-2Rγ	[12]
		miR-23a	Functional blocking of miR-23a in human cytotoxic T lymphocytes hindering tumor progression	BLIMP-1	[13]

NK: Natural killer; NPC: Nasopharyngeal carcinoma.

In addition to their potential use as therapeutic targets, miRNAs can act as potential biomarkers for cancer management. D’Angelo et al. [14] reported a therapeutic role for miRNAs as novel biomarkers in gastrointestinal carcinogenesis. Matuszcak et al. [15] also found that miRNAs are potentially clinically applicable as biomarkers for chemoresistance in gastric cancer.

3. Expert opinion

In recent years, databases of identified miRNAs have advanced our understanding on the relevant signaling pathways in the initiation of drug resistance in cancer cells and facilitated the development of effective targeted therapies combining miRNA therapy with personalized medicine. Dysregulated miRNA levels is a prognostic biomarker in addition to somatic germ-line mutations, changes in DNA methylation status and the presence of circulating tumor cells in the blood. From a cancer treatment perspective, some mutational hotspots represent ideal targets in clinical practice for personalized oncotherapy, for example, tyrosine kinase inhibitors for chronic myeloid leukemia, anaplastic lymphoma kinase inhibitors for lung cancer with EML4–ALK fusion, EGFR inhibitors for EGFR-mutated lung cancer, and HER2/neu blockage in HER2/neu-positive breast cancer [16]. In addition to conventional diagnosis of a disease, the selection of a targeted therapy is based on the particular genetic background of the specific group in a population. There is a paradigm shift in molecular cancer classification.

Recent technological advances in high-throughput genomic profiling by next-generation sequencing have provided rapid and comprehensive molecular analytical results for individual cancer genomes [17]. The expansion of next-generation sequencing technologies provides compelling evidence and promotes its adoption into clinical areas [18]. The care and treatment of cancer patients are approaching a biomarker-driven treatment algorithm that is based on the molecular signature of the tumor. Efforts to validate sequence variants in mutant genes in the setting of clinical oncology are essential to enhance our understanding as well as to determine causality for the phenotypic disorders of cancer patients. With these technological advances, miRNAs are establishing their potential role in combination therapy for cancer, as either therapeutic targets or predictive biomarkers.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.