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[Preprint]. 2023 Feb 27:2023.02.24.529976. [Version 1] doi: 10.1101/2023.02.24.529976

Differentially deregulated microRNAs contribute to ultraviolet radiation-induced photocarcinogenesis through immunomodulation: An-analysis of microRNAs expression profiling

Anshu Agarwal 1,2,3,†, Vikash Kansal 4,†, Humaira Farooqi 3,*, Vijay Kumar Singh 2,*, Ram Prasad 1,*
PMCID: PMC10002698  PMID: 36909651

Abstract

MicroRNAs (miRNAs) are short non-coding RNA molecules (18–25 nucleotides) that regulate several fundamental biological processes. Emerging evidence has shown more than 1500 miRNAs functions in the cell cycle, proliferation, apoptosis, oxidative stress, immune response, DNA damage, and epigenetics alterations. miRNAs are bidirectionally in nature and act as a tumor suppressor and as an oncogene through crosstalk between tumor cells and immune cells. Although the roles of miRNAs in several cancers are well studied, little is known about ultraviolet B (UVB) radiation-induced skin cancer. Here, we performed a comprehensive screening of 1281 miRNAs in tumor tissues and compared their expression with normal skin. Our results demonstrate that the expression levels of 587 miRNAs were altered in tumor tissues compared to their expression in normal skin. The expression of 337 miRNAs was upregulated from 1.5–12 folds, while the expression of 250 miRNAs was downregulated up to 1.5–10 folds in tumors. Further, intraperitoneal injection of a mimic of down-regulated miR-15b (30nM) and an inhibitor of upregulated miR-133a (20nM) protect UVB-induced suppression of contact hypersensitivity (CHS) response. In conclusion, we identified a network of altered miRNAs in tumors that can serve as prognostic biomarkers and therapeutic targets to manage photocarcinogenesis effectively.

Keywords: Meta-analysis, microRNAs, skin tumor, photocarcinogenesis

1. Introduction

Skin, an important protective shield of the entire body, acts as a barrier to block the penetration of ultraviolet radiation (UV) and contact with foreign particles. Solar UV radiation is one of the critical risk factors that initiate carcinogenic events and promote skin cancer by inducing inflammatory responses, oxidative stress, immunosuppression, DNA damage, and gene mutations, all of which have been implicated in a variety of skin diseases, including the development of skin cancers [1–4]. UV radiation-induced inflammation plays a crucial role in all three stages of tumor development (initiation, promotion, and progression). Chronic exposure to UV radiation is a well-recognized etiological factor for all types of skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, and which accounts for the approximately 1.3 million new cases of skin cancer each year in the USA [5]. The incidence of skin cancer is nearly equal to other malignancies in all other organs [6], thus representing a significant public health problem. Skin cancer development and progression is a complex process accompanied by multiple molecular changes at cellular levels. Despite intensive investigations, the precise mechanisms by which UVB radiation causes skin cancer remains unclear. Therefore, to uncover the molecular mechanisms involved in photocarcinogenesis, more novel makers must be discovered in this area.

MicroRNAs (miRNAs) are small non-coding RNA molecules (18–25 nucleotides) that play an essential role in various physiological functions in mammals and other multicellular organisms. A single miRNA targets up to hundreds of mRNAs. Approximately 30–60% of all human genes are affected by miRNA regulation. It has been reported that miRNAs affect several diseases and cancer-related processes such as proliferation, cell cycle control, apoptosis, differentiation, migration, and metabolism [7–10] and function as oncogenes or tumor-suppressor genes. This dual role of miRNAs has been reported in various studies. As tumor suppressors, they repress oncogenic targets but are usually downregulated in cancer tissues [11]. Others are upregulated and have a stimulating role in cancer progression [12,13]. The biogenesis of miRNA is a three-step process; (i) transcription of primary miRNA (pri-miRNA) from the miRNA genes, (ii) partially processed precursor miRNA (pre-miRNA) in nuclei, and (iii) the generation of mature miRNAs into the cytoplasm (Fig. 1). Pri-miRNA is typically large transcripts and forms stem-loop structures.

Figure 1:

Figure 1:

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Biogenesis of miRNAs. (A) In the nucleus, ribonuclease enzyme II transcribes the pri-miRNA transcript. Drosha and its co factor Pasha form the microprocessor complex that cleaves pri-miRNA transcript into pre-miRNA which share a stem loop structure. These pre-miRNAs are transported by exportin-5 into cytoplasm from nucleus. (B) In the cytoplasm, Dicer unwind the miRNA duplex into mature miRNA and complementary strand (miRNA*, which rapidly degraded), and loaded mature miRNA into RNA-induced silencing complex (RISC). (C) Depending on the degree of complementarity between the target mRNA and the miRNA, the binding ether stops the translation by cleaving the target mRNA or suppress translation by binding to impeding ribosomal reading of the mRNA (incomplete complementarity). miRNA, microRNA; pri-miRNA, primary microRNA; pre-miRNA, precursor -microRNA; RISC, RNA-induced silencing complex.

Further, the stem-loop is cleaved off by the microprocessor machinery. Drosha (ribonuclease enzyme III) and its cofactor Pasha (DiGeorge syndrome critical region gene 8) form pre-miRNA (~60–100 nucleotide). After successful cleavage, the pre-miRNA is bound by exportin-5 and exported from the nucleus to the cytoplasm [14,15]. In the cytoplasm, pre-miRNA undergoes the next step of processing mediated by Dicer to produce the mature miRNA. The Dicer (ribonuclease enzyme III) cleaves RNAs into ~22 nucleotide products [16,17]. After cleavage, one strand of the miRNA duplex is preferentially incorporated into the RISC complex and binds to Argonaute (AGO) protein. The other strand, shown in Fig. 1, referred to as miRNA* (a complementary strand labeled by a star in the figure), normally degraded.

In some cases, miRNAs* can also be functional [18]. Although miRNAs are tiny in size but heavily involved in mammalian development through the regulation of various genes and represent a novel class of potential biomarkers or therapeutic targets. As a new layer of gene regulation mechanism, miRNAs have diverse functions, and deregulation alters normal cell growth and development, leading to various disorders, including human cancers. MiRNAs play a central role in immune regulation by modulating immune cells [19]. The expression of miRNAs has been demonstrated to be highly specific for tissues and developmental stages. Here to determine the effect of UVB radiation on miRNAs expression and their role in photocarcinogenesis, we performed a miRNAs expression profiling for more than 1000 miRNAs and provided a wide range of altered miRNAs expression in tumors.

2. Results

2.1. UVB radiation-induced alterations in miRNAs expression

First, to determine the effect of UVB radiation on miRNA expression in skin tumors, we performed miRNA array profiling using 7th-generation sequencing, which contains 3100 capture probes targeting human, mouse, and rat miRNAs registered in the miRBASE 18.0. These 3100 capture probes target 1281 mouse miRNAs (Fig. 2A). Our miRNAs profiling revealed that the expression levels of 587 miRNAs were changed in UVB-induced tumors, while the levels of 694 miRNAs remained unchanged (Fig. 2B). Out of 587 altered miRNAs, the expression levels of 250 miRNAs were downregulated, while the expression levels of 337 miRNAs were upregulated (Fig. 2C) in tumors.

Figure 2:

Figure 2:

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Total number of miRNAs profiled in tumors and normal skin of SKH-1 hairless mice. SKH-1 hairless mice were exposed to UVB radiation (180mJ/cm2) for up to 24 weeks, and tumor and skin tissue were harvested for miRNAs isolation using Trizol-chloroform extraction method. (A) Total number of miRNAs measured in tumors and skin tissues, (B) The number of altered miRNAs expression in tumors, (C)The number of downregulated, upregulated and aberrantly expressed miRNAs.

2.2. Down-regulation of miRNAs in UVB tumors

The loss of miRNA expression is closely related to tumor cell growth and has been implicated in tumorigenesis [20]. Therefore, we next identified the total number of down-regulated miRNAs in the tumor tissue. As shown in Fig. 3A, Out of 250 down-regulated miRNAs (Table-1), the expression of 165 miRNAs was reduced between 1.01–2.0 fold, while about 55 miRNAs’ expression was reduced between 2.01–4.0 fold in the tumors. The expression of 17 miRNAs was decreased within the range of 4.01–6.0 fold, and 13 miRNAs were downregulated more than 6 folds in the tumors compared to the normal skin. These down-regulated miRNAs may act as tumor suppressors.

Figure 3:

Figure 3:

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Graphical representation of fold change in the expression of miRNAs in UVB induced tumors. Graph showing difference in down regulated miRNAs (A) and upregulated miRNAs (B).

Table 1:

Fold change expression of down-regulated miRNAs in UVB-induced tumors (UT). Data were compared with non-UVB exposed normal skin (CS).

Probe ID Annotation AvgHy3 UT CS logFC Fold Change (CS vs. UT)
42866 mmu-miR-451a 14.22 3.31 −3.46 −6.77 −109.45
29802 mmu-miR-144-3p 11.65 3.57 −2.79 −6.36 −82.18
32946 mmu-miR-3107-5p/mmu-miR-486-5p 9.44 3.02 −1.21 −4.23 −18.75
169104 mmu-miR-5099 12.49 2.80 −1.12 −3.91 −15.05
169268 mmu-miR-5112 8.49 2.45 −1.07 −3.52 −11.48
17280 mmu-miR-15b-5p 11.39 2.70 −0.71 −3.41 −10.66
148472 mmu-miR-201-5p 8.55 2.36 −1.05 −3.41 −10.62
42682 mmu-miR-25-3p 9.25 2.64 −0.66 −3.30 −9.84
46320 mmu-miR-31-3p 9.29 2.46 −0.62 −3.08 −8.46
30687 mmu-miR-93-5p 10.13 2.50 −0.47 −2.97 −7.85
10967 mmu-miR-16-5p 13.27 2.54 −0.41 −2.95 −7.72
19599 mmu-miR-106a-5p 10.38 2.37 −0.49 −2.86 −7.25
148578 mmu-miR-541-3p 10.32 2.38 −0.44 −2.82 −7.07
169075 mmu-miR-92a-3p 9.63 2.18 −0.50 −2.68 −6.40
11052 mmu-miR-31-5p 10.26 2.23 −0.31 −2.54 −5.81
145845 mmu-miR-20a-5p 10.97 2.06 −0.47 −2.54 −5.80
148344 mmu-miR-669l-3p 12.23 2.10 −0.39 −2.49 −5.61
42640 mmu-miR-20b-5p 9.30 1.96 −0.49 −2.45 −5.45
169336 mmu-miR-17-5p 10.42 2.04 −0.40 −2.44 −5.43
10947 mmu-miR-142-3p 12.53 1.96 −0.39 −2.36 −5.12
10997 mmu-miR-19a-3p 9.96 1.88 −0.46 −2.34 −5.06
42630 mmu-miR-140-3p 9.88 2.09 −0.24 −2.32 −5.01
148101 mmu-miR-669d-2-3p/mmu-miR-669d-3p 12.42 1.98 −0.33 −2.31 −4.96
19603 SNORD13 9.85 2.00 −0.31 −2.31 −4.96
27720 mmu-miR-15a-5p 12.24 2.15 −0.14 −2.29 −4.91
19582 mmu-miR-106b-5p 11.34 1.99 −0.26 −2.25 −4.75
146164 mmu-miR-1958 11.82 1.95 −0.16 −2.12 −4.34
146155 mmu-miR-2137 12.40 1.96 −0.15 −2.12 −4.33
14302 mmu-miR-374b-5p/mmu-miR-374c-5p 7.96 1.83 −0.28 −2.11 −4.32
147506 mmu-miR-21a-5p 13.80 1.25 −0.80 −2.04 −4.12
46204 SNORD38B 9.68 1.88 −0.12 −2.01 −4.01
145852 mmu-miR-210-3p 9.08 1.89 −0.07 −1.96 −3.89
18739 mmu-miR-186-5p 7.64 1.92 −0.03 −1.95 −3.87
13143 mmu-miR-301a-3p 8.53 1.87 −0.04 −1.91 −3.76
14290 mmu-miR-541-5p 8.20 1.53 −0.37 −1.90 −3.72
13147 mmu-miR-96-5p 8.59 1.80 −0.09 −1.89 −3.70
168556 mmu-miR-3096b-5p 9.50 1.50 −0.35 −1.86 −3.62
11024 mmu-miR-223-3p 11.55 1.80 −0.04 −1.85 −3.59
168706 mmu-miR-5129-5p 8.60 1.33 −0.50 −1.84 −3.57
148233 mmu-miR-3096a-3p 10.79 1.38 −0.44 −1.82 −3.53
11245 mmu-miR-433-5p 10.60 1.48 −0.33 −1.81 −3.51
168880 mmu-miR-489-5p 7.39 1.16 −0.65 −1.81 −3.51
14289 mmu-miR-540-3p 9.68 1.43 −0.38 −1.81 −3.50
148098 mmu-miR-374b-5p 8.54 1.70 −0.09 −1.79 −3.46
148238 mmu-miR-3096a-5p 9.47 1.59 −0.18 −1.78 −3.43
148528 mmu-miR-196a-1-3p 8.40 1.15 −0.63 −1.78 −3.43
145798 mmu-miR-142-5p 10.46 1.55 −0.22 −1.78 −3.43
148087 mmu-miR-669d-2-3p 9.70 1.63 −0.03 −1.66 −3.16
146192 mmu-miR-669m-3p 11.14 1.75 0.10 −1.65 −3.14
10998 mmu-miR-19b-3p 10.88 1.55 −0.10 −1.65 −3.13
42811 mmu-miR-542-5p 8.23 1.68 0.07 −1.61 −3.04
148035 mmu-miR-3084-5p 9.95 1.55 −0.04 −1.59 −3.00
169340 mmu-miR-3096a-3p/mmu-miR-3096b-3p 9.99 1.00 −0.53 −1.53 −2.88
146012 mmu-miR-1949 9.75 0.93 −0.52 −1.44 −2.72
145633 mmu-let-7d-3p 8.99 1.36 −0.07 −1.43 −2.69
46917 mmu-miR-205-5p 13.85 1.41 0.01 −1.40 −2.64
4700 mmu-miR-140-5p 8.84 1.41 0.02 −1.40 −2.64
17608 mmu-miR-425-5p 7.84 1.30 −0.10 −1.40 −2.63
17427 mmu-miR-200c-3p 10.57 1.42 0.02 −1.40 −2.63
19585 mmu-miR-148b-3p 8.26 1.43 0.06 −1.37 −2.59
27558 mmu-miR-155-5p 7.66 1.31 −0.02 −1.33 −2.52
169347 mmu-miR-5622-5p 9.16 1.22 −0.05 −1.26 −2.40
42702 mmu-miR-30c-1-3p 7.63 1.24 −0.02 −1.26 −2.40
17610 mmu-miR-677-5p 8.36 1.27 0.02 −1.25 −2.38
10975 mmu-miR-182-5p 8.49 1.17 −0.07 −1.24 −2.36
42919 mmu-miR-203-5p 8.96 1.40 0.16 −1.23 −2.35
148484 mmu-miR-3084-3p 11.53 1.02 −0.20 −1.22 −2.33
9938 mmu-let-7i-5p 11.74 1.21 −0.01 −1.21 −2.32
10946 mmu-miR-141-3p 10.95 1.17 −0.03 −1.20 −2.30
19007 SNORD3@ 12.94 0.93 −0.26 −1.20 −2.30
148676 mmu-miR-1186b 10.48 0.92 −0.28 −1.20 −2.29
169277 mmu-miR-3970 9.60 1.06 −0.12 −1.17 −2.26
145661 SNORD65 8.08 1.06 −0.09 −1.15 −2.22
27533 mmu-miR-320-3p 8.77 1.31 0.16 −1.15 −2.22
46438 mmu-let-7g-5p 11.41 1.35 0.21 −1.14 −2.20
42730 mmu-miR-423-3p 8.51 0.94 −0.18 −1.12 −2.17
29490 mmu-miR-7a-5p 10.34 1.00 −0.10 −1.09 −2.13
42571 mmu-miR-129-1-3p 7.53 0.91 −0.17 −1.08 −2.11
168966 mmu-miR-28a-5p/mmu-miR-28c 8.67 1.01 −0.06 −1.07 −2.10
168872 mmu-miR-24-1-5p 9.44 1.14 0.07 −1.06 −2.09
11022 mmu-miR-221-3p 9.36 1.08 0.03 −1.06 −2.08
31388 mmu-miR-291a-5p 10.55 0.73 −0.31 −1.05 −2.07
17854 mmu-miR-106b-3p 8.53 1.18 0.14 −1.04 −2.06
168859 mmu-miR-3962 10.72 1.20 0.17 −1.03 −2.04
10985 mmu-miR-191-5p 9.98 1.25 0.22 −1.03 −2.04
29190 mmu-miR-708-5p 8.99 1.28 0.27 −1.00 −2.01
42707 mmu-miR-294-5p 12.23 0.57 −0.43 −1.00 −2.00
146004 mmu-miR-2136 7.47 1.12 0.13 −0.99 −1.99
148051 mmu-miR-770-3p 7.89 0.97 −0.01 −0.97 −1.96
146111 mmu-miR-767 8.42 0.85 −0.12 −0.97 −1.96
147199 mmu-miR-27b-3p 11.90 0.91 −0.05 −0.96 −1.94
28547 mmu-miR-675-5p 9.89 0.94 0.00 −0.95 −1.93
11184 mmu-miR-99b-5p 9.63 0.95 0.00 −0.94 −1.92
11023 mmu-miR-222-3p 9.70 0.92 −0.02 −0.94 −1.92
148416 mmu-miR-3102-5p 7.87 0.68 −0.26 −0.93 −1.91
169330 mmu-miR-23b-3p 13.09 1.01 0.12 −0.89 −1.86
28450 mmu-miR-291b-5p 9.91 0.72 −0.17 −0.89 −1.85
145663 SNORD68 11.57 0.92 0.03 −0.89 −1.85
11260 mmu-miR-151-5p 8.24 1.04 0.16 −0.88 −1.84
168630 mmu-miR-5121 9.19 0.57 −0.30 −0.87 −1.83
17752 mmu-let-7f-5p 9.95 1.18 0.31 −0.87 −1.83
10990 mmu-miR-196a-5p 7.51 0.40 −0.45 −0.86 −1.81
145666 SNORD110 8.73 0.83 −0.02 −0.85 −1.81
19008 SNORD2 12.27 0.61 −0.24 −0.84 −1.79
146199 mmu-miR-1961 8.41 1.05 0.21 −0.84 −1.79
146112 mmu-miR-30b-5p 11.23 1.15 0.31 −0.83 −1.78
11256 mmu-miR-470-5p 9.04 0.79 −0.04 −0.83 −1.78
145968 mmu-let-7d-5p 11.44 1.02 0.19 −0.83 −1.77
27575 mmu-miR-711 9.56 1.17 0.35 −0.82 −1.77
148523 mghv-miR-M1-8-3p 11.82 0.50 −0.31 −0.81 −1.75
10988 mmu-miR-194-5p 7.42 0.72 −0.08 −0.80 −1.74
10936 mmu-miR-130b-3p 7.66 0.69 −0.11 −0.80 −1.74
146087 mmu-miR-1894-3p 8.36 0.88 0.08 −0.80 −1.74
30831 mmu-miR-804 7.40 1.21 0.42 −0.79 −1.73
17506 mmu-miR-24-3p 13.49 1.04 0.25 −0.78 −1.72
147162 mmu-let-7a-5p 11.08 0.98 0.20 −0.78 −1.72
17478 mmu-miR-429-3p 8.89 1.14 0.37 −0.78 −1.71
146172 mmu-miR-1892 8.93 0.65 −0.12 −0.77 −1.70
42953 mmu-miR-101b-3p 9.31 0.99 0.23 −0.76 −1.69
17597 mmu-miR-467b-3p 9.91 1.00 0.25 −0.74 −1.67
148100 mmu-miR-1947-3p 12.96 0.37 −0.36 −0.73 −1.66
145859 mmu-miR-33-5p 9.39 0.79 0.06 −0.73 −1.65
11020 mmu-miR-22-3p 12.57 0.93 0.21 −0.72 −1.65
28966 mmu-miR-574-3p 8.91 0.73 0.02 −0.71 −1.64
42923 mmu-miR-30c-5p 11.58 0.95 0.26 −0.69 −1.61
148107 mmu-miR-3104-3p 7.93 0.92 0.23 −0.69 −1.61
168824 mmu-miR-5100 15.78 0.89 0.20 −0.68 −1.61
168842 mmu-miR-5105 7.38 0.68 0.01 −0.67 −1.59
28191 mmu-miR-30e-5p 10.73 0.95 0.28 −0.67 −1.59
145838 mmu-miR-125b-1-3p 8.42 0.74 0.07 −0.67 −1.59
148362 mmu-miR-592-3p 9.08 1.06 0.40 −0.66 −1.58
42605 mmu-miR-503-3p 11.29 0.54 −0.12 −0.66 −1.58
168819 mmu-miR-200a-3p 10.35 0.87 0.22 −0.65 −1.57
145753 mmu-miR-484 7.61 0.82 0.18 −0.64 −1.56
42827 mmu-miR-652-3p 8.04 0.75 0.13 −0.62 −1.54
145897 mmu-miR-92b-3p 8.50 0.23 −0.39 −0.62 −1.53
169190 mmu-miR-5117-3p 11.20 0.73 0.11 −0.61 −1.53
169105 mmu-miR-3963 15.95 1.14 0.53 −0.61 −1.53
11053 mmu-miR-32-5p 8.82 0.78 0.18 −0.60 −1.52
145993 mmu-miR-1899 8.41 0.60 0.00 −0.59 −1.51
19600 mmu-miR-17-3p 9.34 0.41 −0.17 −0.59 −1.50
11215 mmu-miR-292-3p 7.57 1.95 1.37 −0.59 −1.50
145701 mmu-miR-668-3p 7.90 0.81 0.23 −0.58 −1.49
14301 mmu-miR-361-5p 9.27 0.80 0.22 −0.58 −1.49
14285 mmu-miR-487b-3p 8.04 0.56 −0.01 −0.58 −1.49
148059 mmu-miR-493-5p 8.92 0.24 −0.33 −0.57 −1.48
169248 mmu-miR-5108 7.39 0.40 −0.16 −0.57 −1.48
169250 mmu-miR-5109 13.60 0.69 0.13 −0.56 −1.48
148197 mmu-miR-3081-5p 8.34 0.46 −0.10 −0.56 −1.47
42888 mmu-miR-875-3p 12.08 0.47 −0.09 −0.56 −1.47
168708 mmu-miR-296-5p 7.47 0.78 0.22 −0.56 −1.47
11227 mmu-miR-329-3p 9.38 0.98 0.43 −0.54 −1.46
46210 mmu-miR-1249-3p 7.70 1.14 0.61 −0.53 −1.44
169246 mmu-miR-5618-5p 7.82 0.47 −0.05 −0.52 −1.44
17489 mmu-miR-710 10.34 0.54 0.03 −0.51 −1.43
30768 mmu-miR-674-5p 9.18 0.57 0.07 −0.50 −1.42
10138 mmu-miR-130a-3p 10.45 0.80 0.31 −0.49 −1.40
19606 SNORD12 8.89 0.30 −0.18 −0.48 −1.39
168807 mmu-miR-3473c 7.55 0.59 0.12 −0.47 −1.39
10955 mmu-miR-148a-3p 8.03 0.50 0.04 −0.46 −1.38
169374 mmu-miR-184-5p 11.08 0.34 −0.12 −0.46 −1.38
148261 mmu-miR-208a-5p 7.23 0.46 0.00 −0.46 −1.38
168762 mmu-miR-3964 7.99 0.18 −0.27 −0.45 −1.37
11182 mmu-miR-98-5p 10.38 0.77 0.34 −0.44 −1.35
11234 mmu-miR-350-3p 7.72 0.57 0.14 −0.44 −1.35
168586 mmu-miR-34a-5p 9.78 0.11 −0.32 −0.43 −1.35
46483 mmu-miR-27a-3p 11.82 0.44 0.01 −0.43 −1.34
147186 mmu-miR-200b-3p 10.53 0.67 0.27 −0.41 −1.33
46636 mcmv-miR-M23-1-5p 8.00 −0.09 −0.49 −0.39 −1.31
13140 mmu-miR-138-5p 8.44 0.41 0.04 −0.37 −1.29
148654 mmu-miR-184-3p 7.29 0.47 0.10 −0.37 −1.29
10986 mmu-miR-193a-3p 9.90 0.60 0.23 −0.37 −1.29
21498 mmu-miR-654-3p 7.21 0.63 0.26 −0.36 −1.29
19605 SNORD6 7.44 0.69 0.34 −0.34 −1.27
148046 mmu-miR-344-5p 7.42 −0.03 −0.37 −0.34 −1.27
42744 mmu-miR-23a-3p 13.14 0.65 0.32 −0.33 −1.26
42636 mmu-miR-28a-3p 7.39 0.48 0.16 −0.32 −1.25
148391 mmu-miR-3068-5p 8.04 0.07 −0.25 −0.31 −1.24
148424 mmu-miR-201-3p 8.42 0.14 −0.17 −0.31 −1.24
46251 mmu-miR-1193-3p 7.35 0.03 −0.28 −0.31 −1.24
42724 mmu-miR-34b-3p 9.92 0.23 −0.08 −0.30 −1.24
145643 mmu-miR-382-5p 7.96 0.47 0.16 −0.30 −1.24
17810 mmu-miR-29b-1-5p 9.05 0.38 0.07 −0.30 −1.23
146065 mmu-miR-1927 7.27 0.35 0.05 −0.30 −1.23
148218 mghv-miR-M1-11-3p 7.84 0.42 0.13 −0.29 −1.22
148485 mghv-miR-M1-12-3p 8.22 0.40 0.11 −0.29 −1.22
146106 mmu-miR-1931 8.20 0.19 −0.10 −0.29 −1.22
42494 mmu-miR-712-3p 7.58 0.27 −0.02 −0.29 −1.22
42452 mmu-miR-141-5p 7.69 0.33 0.05 −0.28 −1.22
148166 mmu-miR-3069-3p 8.84 0.28 0.00 −0.28 −1.21
42879 mmu-miR-92a-2-5p 8.29 0.65 0.38 −0.27 −1.21
42488 mmu-miR-466h-5p 7.32 0.92 0.66 −0.26 −1.20
14328 mmu-miR-124-3p 7.45 0.50 0.24 −0.25 −1.19
148470 mmu-miR-1264-3p 10.00 0.12 −0.13 −0.25 −1.19
148370 mmu-miR-466n-3p 9.63 0.22 −0.02 −0.24 −1.18
10919 mmu-miR-103-3p 10.69 0.57 0.32 −0.24 −1.18
148172 mmu-miR-216a-3p 8.11 −0.10 −0.32 −0.23 −1.17
42570 mmu-miR-194-2-3p 7.35 0.33 0.11 −0.22 −1.16
42769 mmu-let-7b-3p 7.38 0.21 0.01 −0.20 −1.15
29852 mmu-miR-9-3p 7.32 0.08 −0.12 −0.19 −1.14
145676 mmu-miR-30e-3p 8.54 0.50 0.31 −0.19 −1.14
13150 mmu-miR-322-5p 8.43 0.36 0.17 −0.19 −1.14
146133 mmu-miR-1936 8.27 0.10 −0.09 −0.18 −1.14
19013 SNORD14B 7.68 0.42 0.24 −0.18 −1.13
168566 mmu-miR-5625-3p 8.24 −0.29 −0.46 −0.17 −1.13
145638 mmu-miR-29a-5p 8.21 0.47 0.30 −0.17 −1.12
148179 mmu-miR-3095-3p 10.46 0.04 −0.12 −0.16 −1.12
168687 mmu-miR-29a-3p 12.14 0.29 0.12 −0.16 −1.12
168662 mmu-miR-5132-5p 8.87 −0.01 −0.17 −0.16 −1.12
146086 mmu-miR-30a-5p 10.06 0.62 0.47 −0.15 −1.11
27536 mmu-miR-190a-5p 7.52 0.87 0.73 −0.15 −1.11
17953 mmu-miR-183-3p 10.40 0.07 −0.08 −0.15 −1.11
145640 mmu-miR-328-3p 8.53 0.02 −0.13 −0.14 −1.10
33114 mmu-miR-455-3p 7.46 0.05 −0.09 −0.14 −1.10
17273 mghv-miR-M1-6-3p 8.28 0.67 0.53 −0.14 −1.10
28019 mmu-miR-10a-3p 7.92 0.14 0.01 −0.13 −1.09
148242 mmu-miR-205-3p 8.63 −0.14 −0.27 −0.13 −1.09
148121 mmu-miR-155-3p 9.32 0.18 0.05 −0.13 −1.09
11251 mmu-miR-465a-5p 7.75 0.68 0.56 −0.13 −1.09
168968 mmu-miR-147-3p 8.94 0.27 0.15 −0.12 −1.09
147283 mmu-miR-137-5p 8.05 0.50 0.39 −0.12 −1.08
19596 mmu-miR-30d-5p 9.79 0.59 0.47 −0.12 −1.08
17818 mmu-miR-27a-5p 7.25 0.30 0.18 −0.11 −1.08
148546 mmu-miR-500-5p 7.30 0.33 0.21 −0.11 −1.08
146008 mmu-miR-26b-5p 11.47 0.55 0.43 −0.11 −1.08
148646 mmu-miR-467a-3p 11.52 0.27 0.16 −0.11 −1.08
168797 mmu-miR-3968 11.65 −0.28 −0.38 −0.10 −1.07
42808 mmu-miR-874-3p 7.44 −0.12 −0.22 −0.10 −1.07
42738 mmu-miR-340-3p 7.65 0.19 0.10 −0.09 −1.07
10923 mmu-miR-107-3p 10.15 0.39 0.30 −0.09 −1.06
42950 mmu-miR-24-2-5p 9.57 0.38 0.30 −0.09 −1.06
11040 mmu-miR-29b-3p 11.90 0.32 0.24 −0.08 −1.06
17825 mmu-miR-338-5p 7.72 0.13 0.05 −0.08 −1.06
42532 mmu-miR-22-5p 9.41 0.45 0.38 −0.08 −1.05
148225 mmu-miR-3102-5p.2-5p 7.38 −0.03 −0.09 −0.07 −1.05
10977 mmu-miR-183-5p 9.22 −0.11 −0.17 −0.06 −1.04
14272 mmu-miR-542-3p 7.86 0.34 0.28 −0.06 −1.04
42464 mghv-miR-M1-2-3p 9.14 0.67 0.62 −0.05 −1.04
148128 mmu-miR-3090-5p 9.16 −0.10 −0.15 −0.05 −1.03
11078 mmu-miR-365-3p 9.43 0.42 0.37 −0.04 −1.03
16681 mmu-miR-721 9.22 −0.05 −0.09 −0.04 −1.02
30787 mmu-miR-125b-5p 12.75 0.37 0.34 −0.03 −1.02
148689 mmu-miR-3099-5p 9.18 0.18 0.15 −0.03 −1.02
42929 mmu-miR-25-5p 10.96 0.71 0.69 −0.03 −1.02
17942 mmu-miR-125a-3p 7.67 0.02 −0.01 −0.03 −1.02
42804 mmu-miR-712-5p 8.16 0.00 −0.02 −0.02 −1.02
46292 mmu-miR-5097 11.74 −0.68 −0.69 −0.02 −1.01
148303 mmu-miR-3106-5p 7.42 −0.26 −0.27 −0.02 −1.01
169060 mmu-miR-3961 12.40 −0.25 −0.27 −0.01 −1.01
148270 mmu-miR-669b-3p 11.78 0.28 0.27 −0.01 −1.01
145678 mmu-miR-150-5p 9.57 0.11 0.10 −0.01 −1.01
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2.3. Upregulation of miRNAs in UVB tumors

UV radiation causes several mutations in gene status to induce tumors, such as the p53 mutation regulated by miRNAs. In our miRNAs profiling results, we observed that the levels of 3377 miRNAs were upregulated in tumors (Fig. 3B, Table 2). In the tumor tissue, out of 337 upregulated miRNAs, the expression of 285 miRNAs was increased up to 2.0 fold, while about 45 miRNAs’ expression was increased between 2.01–4.0 fold. The expression of 7 miRNAs was highly upregulated more than 6 folds in the UVB-induced tumors compared with their expression in the normal skin. These upregulated miRNAs may act as an oncogene to promote photocarcinogenesis.

Table 2:

Fold change expression of up-regulated miRNAs in UVB-induced tumors (UT). Data were compared with non-UVB exposed normal skin (CS).

Probe ID Annotation AvgHy3 UT CS logFC Fold Change (CS vs UT)
42927 mmu-miR-673-3p 9.40 0.19 0.19 0.01 1.01
14288 mmu-miR-503-5p 10.65 0.07 0.08 0.01 1.01
148076 mmu-miR-3103-5p 7.90 −0.14 −0.12 0.02 1.01
146029 mmu-miR-365-2-5p 7.37 0.01 0.03 0.02 1.01
42609 mmu-miR-135a-1-3p 7.89 −0.18 −0.16 0.02 1.01
148286 mmu-miR-3066-3p 7.32 −0.07 −0.05 0.03 1.02
148656 mmu-miR-3099-3p 8.54 0.18 0.20 0.03 1.02
13148 mmu-miR-195a-5p 11.20 0.40 0.43 0.03 1.02
42475 mmu-miR-221-5p 8.07 −0.14 −0.10 0.04 1.02
168596 mmu-miR-5620-3p 8.23 −0.22 −0.18 0.04 1.03
148200 mmu-miR-3100-3p 12.41 −0.15 −0.12 0.04 1.03
148468 mmu-miR-677-3p 11.21 0.12 0.16 0.04 1.03
148114 mmu-miR-26a-2-3p 7.39 0.04 0.08 0.04 1.03
146082 mmu-miR-1956 8.11 0.14 0.18 0.04 1.03
145846 mmu-let-7e-5p 12.12 0.13 0.18 0.05 1.03
146099 mmu-miR-1950 7.59 0.02 0.06 0.05 1.03
145820 mmu-let-7c-5p 12.26 0.39 0.44 0.05 1.04
11074 mmu-miR-34c-5p 8.99 0.13 0.19 0.05 1.04
42474 mmu-miR-362-3p 7.88 0.11 0.16 0.06 1.04
148146 mmu-miR-3076-3p 8.31 0.03 0.09 0.06 1.04
28979 mmu-miR-670-5p 7.28 0.31 0.37 0.06 1.04
148450 mmu-miR-210-5p 7.80 −0.27 −0.21 0.06 1.04
169394 mmu-miR-1843a-5p 7.63 0.03 0.09 0.06 1.04
11231 mmu-miR-345-5p 8.78 −0.37 −0.30 0.07 1.05
148614 mmu-miR-7a-2-3p 8.45 −0.19 −0.11 0.07 1.05
148052 mmu-miR-374c-3p 7.94 0.28 0.37 0.08 1.06
146088 mmu-miR-1983 12.82 −0.25 −0.16 0.09 1.06
146143 mmu-miR-1904 7.64 −0.18 −0.08 0.10 1.07
169408 mmu-miR-181d-5p 8.36 −0.02 0.08 0.10 1.07
27565 mmu-miR-423-5p 10.75 −0.06 0.05 0.11 1.08
42902 mmu-miR-185-5p 9.72 −0.07 0.04 0.11 1.08
147165 mmu-let-7b-5p 12.16 0.46 0.58 0.12 1.09
42519 mmu-miR-465c-5p 9.06 −0.24 −0.12 0.12 1.09
42528 mmu-miR-296-3p 8.60 −0.15 −0.03 0.12 1.09
148278 mmu-miR-138-2-3p 9.39 −0.27 −0.14 0.13 1.09
148651 mmu-miR-3072-3p 8.66 0.49 0.62 0.13 1.09
148440 mmu-miR-452-3p 7.41 −0.58 −0.45 0.13 1.09
168876 mmu-miR-1843b-5p 8.00 −0.04 0.10 0.13 1.10
148191 mmu-miR-3081-3p 8.45 −0.40 −0.26 0.14 1.10
148230 mmu-miR-450a-1-3p 9.48 −0.13 0.01 0.14 1.10
17676 mmu-miR-152-3p 8.39 0.07 0.21 0.14 1.10
46774 mcmv-miR-m01-2-5p 8.08 −0.22 −0.07 0.14 1.11
146156 mmu-miR-1960 8.64 −0.07 0.07 0.15 1.11
148097 mmu-miR-329-5p 7.97 −0.17 −0.03 0.15 1.11
148560 mmu-miR-3066-5p 7.88 0.02 0.17 0.15 1.11
17431 mghv-miR-M1-8-5p 11.01 −0.18 −0.02 0.16 1.12
10943 mmu-miR-136-5p 8.34 0.18 0.34 0.16 1.12
148309 mmu-miR-3068-3p 11.98 −0.12 0.05 0.17 1.12
11208 mmu-miR-207 10.85 −0.53 −0.37 0.17 1.12
27572 mmu-miR-298-5p 8.34 −0.32 −0.15 0.17 1.13
17352 mghv-miR-M1-5-5p 9.76 −0.28 −0.10 0.17 1.13
42619 mmu-miR-709 13.63 −0.23 −0.06 0.18 1.13
148630 mmu-miR-3472 7.53 −0.41 −0.23 0.18 1.13
148103 mghv-miR-M1-4-3p 8.40 −0.35 −0.18 0.18 1.13
42790 mmu-miR-337-3p 8.47 −0.48 −0.29 0.19 1.14
11108 mmu-miR-425-3p 7.59 −0.30 −0.11 0.19 1.14
11226 mmu-miR-325-5p 7.92 −0.22 −0.03 0.19 1.14
147701 mmu-miR-491-3p 15.22 −0.11 0.08 0.19 1.14
11235 mmu-miR-351-5p 11.61 −0.41 −0.21 0.19 1.14
148480 mmu-miR-494-5p 7.59 −0.11 0.09 0.19 1.14
42887 mmu-miR-331-3p 8.28 −0.43 −0.23 0.20 1.15
42585 mmu-miR-297a/miR-297b/miR-297c-3p 11.24 0.00 0.20 0.20 1.15
148192 mmu-miR-421-3p 7.94 0.01 0.21 0.20 1.15
168977 mmu-miR-5128 10.04 −0.45 −0.25 0.20 1.15
27574 mmu-miR-705 10.68 −0.29 −0.09 0.20 1.15
11229 mmu-miR-341-3p 9.68 −0.68 −0.47 0.20 1.15
168752 mmu-miR-5627-3p 7.36 −0.20 0.01 0.20 1.15
42670 mmu-miR-500-3p 7.98 −0.02 0.20 0.22 1.16
168828 mmu-miR-5125 10.65 −0.30 −0.08 0.22 1.17
148252 mmu-miR-496a-5p 7.20 −0.12 0.11 0.22 1.17
11065 mmu-miR-335-5p 7.58 0.35 0.58 0.23 1.17
148099 mmu-miR-344h-3p 10.60 −0.28 −0.05 0.23 1.17
42878 mmu-miR-882 12.20 −0.19 0.04 0.23 1.17
168592 mmu-miR-5622-3p 7.35 −0.11 0.12 0.23 1.17
46385 mmu-miR-1186a 8.65 −0.20 0.04 0.24 1.18
145745 mmu-miR-335-3p 12.80 −0.37 −0.13 0.24 1.18
42471 mmu-miR-290-5p 11.89 −0.26 −0.01 0.24 1.18
33596 mmu-miR-126-5p 9.30 0.09 0.33 0.25 1.19
169111 mmu-miR-5616-3p 9.65 −0.29 −0.04 0.25 1.19
148558 mmu-miR-3064-5p 8.42 −0.08 0.16 0.25 1.19
169373 mmu-miR-5626-5p 9.14 0.40 0.65 0.25 1.19
148281 mmu-miR-467e-3p 12.79 −0.19 0.06 0.25 1.19
17632 mmu-miR-691 12.33 −0.19 0.06 0.25 1.19
148226 mmu-miR-467c-3p 10.54 −0.07 0.18 0.25 1.19
28944 mmu-miR-667-3p 11.64 −0.65 −0.39 0.26 1.20
42835 mmu-miR-16-1-3p 8.71 −0.27 −0.01 0.26 1.20
169420 mmu-miR-193b-5p 7.81 −0.47 −0.20 0.26 1.20
17540 mmu-miR-669b-5p 7.90 −0.05 0.22 0.27 1.20
148198 mmu-miR-653-3p 8.88 −0.14 0.13 0.27 1.21
168890 mmu-miR-1306-5p 7.62 −0.34 −0.06 0.27 1.21
148657 mmu-miR-381-5p 7.52 −0.02 0.27 0.28 1.22
17313 mmu-miR-297b-5p 7.58 0.04 0.33 0.28 1.22
42767 mmu-miR-34c-3p 8.97 −0.41 −0.13 0.29 1.22
145692 mmu-miR-499-3p 7.11 −0.25 0.04 0.29 1.22
14316 mmu-miR-664-3p 9.26 −0.40 −0.09 0.30 1.23
148155 mghv-miR-M1-1-5p 7.87 −0.36 −0.05 0.30 1.23
148427 mmu-miR-3101-3p 8.14 −0.15 0.15 0.30 1.24
11202 mmu-miR-151-3p 7.51 −0.38 −0.07 0.31 1.24
11210 mmu-miR-215-5p 7.26 −0.09 0.22 0.31 1.24
146171 mmu-miR-1907 8.02 −0.15 0.16 0.31 1.24
168689 mmu-miR-361-3p 8.92 0.41 0.74 0.33 1.26
148609 mmu-miR-487b-5p 8.40 −0.52 −0.19 0.33 1.26
11044 mmu-miR-302c-3p 7.59 −0.16 0.17 0.34 1.26
42709 mmu-miR-743b-5p 7.87 −0.47 −0.13 0.34 1.27
42445 mmu-miR-693-5p 9.98 −0.43 −0.09 0.34 1.27
17291 mghv-miR-M1-4-5p 11.55 −0.35 −0.01 0.35 1.27
11004 mmu-miR-203-3p 12.94 0.33 0.68 0.35 1.27
28309 mmu-miR-741-3p 8.33 −0.46 −0.11 0.35 1.27
148336 mmu-miR-3071-5p 7.32 −0.44 −0.09 0.35 1.28
11018 mmu-miR-218-5p 7.67 −0.32 0.03 0.35 1.28
17511 mmu-miR-713 9.11 −0.47 −0.12 0.35 1.28
145637 mmu-miR-187-3p 8.06 −0.13 0.22 0.36 1.28
42627 mmu-miR-212-3p 7.80 −0.65 −0.29 0.36 1.28
148473 mmu-miR-3473a 12.66 −0.54 −0.18 0.36 1.28
148575 mmu-miR-700-5p 8.09 −0.36 0.01 0.36 1.29
42739 mmu-miR-339-5p 8.19 −0.31 0.06 0.36 1.29
17433 mmu-miR-679-5p 8.28 −0.36 0.01 0.37 1.29
10306 mmu-miR-146b-5p 10.26 −0.11 0.26 0.37 1.29
148415 mmu-miR-668-5p 7.89 −0.40 −0.03 0.37 1.30
169344 mmu-miR-3473b 15.31 −0.33 0.05 0.38 1.30
148632 mmu-miR-2861 8.98 −0.48 −0.10 0.39 1.31
148548 mmu-miR-3090-3p 7.21 −0.84 −0.45 0.39 1.31
148199 mmu-miR-3102-3p 7.47 0.02 0.42 0.39 1.31
148355 mmu-miR-3077-3p 8.99 −0.46 −0.07 0.40 1.32
169051 mmu-miR-5120 9.84 −0.54 −0.14 0.40 1.32
42502 mmu-miR-204-3p 10.70 −0.37 0.03 0.40 1.32
11093 mmu-miR-379-5p 7.19 −0.21 0.19 0.41 1.33
11105 mmu-miR-378a/miR-378b/miR-378c 10.30 0.34 0.75 0.41 1.33
11014 mmu-miR-214-3p 10.82 −0.55 −0.14 0.41 1.33
146145 mmu-miR-1895 9.98 −0.47 −0.05 0.41 1.33
148531 mmu-miR-544-5p 10.07 −0.45 −0.03 0.42 1.34
148446 mmu-miR-346-3p 11.31 −0.22 0.20 0.42 1.34
42626 mmu-miR-30b-3p 10.70 −0.31 0.11 0.42 1.34
46639 mmu-miR-467f 11.87 −0.33 0.09 0.42 1.34
4610 mmu-miR-126-3p 11.41 −0.17 0.26 0.42 1.34
17422 mmu-miR-695 9.46 0.15 0.58 0.43 1.35
168580 mmu-miR-5626-3p 7.89 −0.41 0.02 0.43 1.35
148036 mghv-miR-M1-3-5p 8.28 −0.56 −0.12 0.44 1.36
17495 mmu-miR-697 10.23 −0.68 −0.23 0.44 1.36
148109 mmu-miR-669a/miR-669o-3p 11.46 −0.20 0.24 0.44 1.36
13485 mmu-miR-10a-5p 9.59 −0.31 0.13 0.44 1.36
42708 mmu-miR-99a-5p 9.62 −0.16 0.30 0.45 1.37
42868 mmu-miR-762 10.25 −0.19 0.26 0.45 1.37
42692 mmu-miR-127-5p 7.33 −0.72 −0.27 0.46 1.37
168713 mmu-miR-5135 7.30 −0.16 0.30 0.46 1.37
10928 mmu-miR-125a-5p 11.22 −0.28 0.17 0.46 1.37
17669 mmu-miR-690 15.12 −0.67 −0.21 0.46 1.37
42687 mmu-miR-883b-5p 10.25 −0.26 0.20 0.46 1.38
147203 mmu-miR-302a-3p 11.41 −0.28 0.18 0.46 1.38
42638 mmu-miR-23a-5p 8.43 −0.47 −0.01 0.47 1.38
169329 mmu-miR-370-3p 7.94 −0.70 −0.23 0.47 1.39
148423 mmu-miR-652-5p 7.29 −0.48 −0.01 0.47 1.39
17898 mmu-miR-99b-3p 9.28 −0.57 −0.09 0.47 1.39
148649 mmu-miR-3470a 9.37 −0.48 0.00 0.48 1.40
46288 mmu-miR-1196-5p 13.09 −0.70 −0.22 0.48 1.40
148094 mmu-miR-669c-3p 12.22 −0.26 0.23 0.49 1.40
148175 mmu-miR-1843a-3p 10.42 −0.65 −0.15 0.49 1.41
168787 mmu-miR-5114 9.60 −0.52 −0.02 0.50 1.41
146176 mmu-miR-1971 12.83 −0.28 0.22 0.50 1.41
148171 mmu-miR-7b-3p 8.62 −0.69 −0.20 0.50 1.41
30033 mmu-miR-877-5p 9.98 −0.38 0.12 0.50 1.41
42658 mmu-miR-681 8.26 −0.40 0.10 0.50 1.42
148210 mmu-miR-3060-3p 9.32 −0.91 −0.40 0.51 1.42
148508 mmu-miR-3062-3p 7.84 −0.66 −0.15 0.51 1.43
148448 mmu-miR-3112-3p 8.04 −0.49 0.03 0.51 1.43
42865 mmu-miR-181a-5p 8.90 −0.07 0.45 0.52 1.43
29650 mmu-miR-714 11.24 −1.02 −0.50 0.52 1.43
27672 mmu-miR-615-3p 9.14 −0.75 −0.23 0.52 1.43
148579 mmu-miR-3544-3p 7.32 −0.35 0.17 0.52 1.44
46205 SNORD48 9.35 −0.48 0.05 0.52 1.44
147198 mmu-miR-26a-5p 9.78 0.03 0.56 0.53 1.44
168738 mmu-miR-5127 8.29 −0.94 −0.42 0.53 1.44
145840 mmu-let-7f-1-3p 8.65 −0.57 −0.04 0.53 1.44
145943 mmu-miR-100-5p 8.06 −0.26 0.27 0.54 1.45
28624 mmu-miR-666-5p 9.25 −1.06 −0.52 0.54 1.45
168794 mmu-miR-5107-5p 9.64 −0.54 0.00 0.54 1.45
17465 mmu-miR-678 9.53 −0.50 0.04 0.54 1.45
42592 mmu-miR-338-3p 8.49 0.07 0.61 0.54 1.46
168688 mmu-miR-1843b-3p 14.11 −1.04 −0.50 0.55 1.46
17918 mmu-miR-222-5p 7.36 −0.82 −0.27 0.55 1.46
30681 mmu-miR-376c-3p 8.09 −0.49 0.07 0.56 1.47
11253 mmu-miR-467d-3p 9.11 −0.23 0.33 0.56 1.47
169053 mmu-miR-130b-5p 7.90 −0.52 0.05 0.56 1.48
148045 mmu-miR-3094-3p 7.19 −0.83 −0.26 0.57 1.48
146195 mmu-miR-2139 8.52 −0.56 0.01 0.57 1.48
42826 mmu-miR-300-5p 13.43 −0.40 0.18 0.58 1.50
168817 mmu-miR-5621-3p 8.37 −0.97 −0.39 0.58 1.50
168740 mmu-miR-5113 13.87 −0.50 0.09 0.59 1.50
42490 mmu-miR-505-5p 9.96 −0.46 0.13 0.59 1.50
146023 mmu-miR-1946b 9.68 −0.28 0.31 0.59 1.51
146130 mmu-miR-1946a 7.64 −0.55 0.07 0.61 1.53
169148 mmu-miR-5130 8.24 −0.71 −0.10 0.61 1.53
42574 mmu-miR-467e-5p 10.21 −0.49 0.13 0.62 1.54
42462 mmu-miR-883a-5p 13.01 −0.50 0.12 0.63 1.54
148022 mmu-miR-664-5p 8.47 −0.58 0.05 0.63 1.55
146147 mmu-miR-1897-5p 14.16 −0.66 −0.03 0.63 1.55
42770 mmu-miR-665-3p 12.72 −0.54 0.12 0.65 1.57
32608 mmu-miR-761 8.58 −0.45 0.20 0.66 1.58
168617 mmu-miR-5131 7.17 −0.59 0.07 0.66 1.58
31026 mmu-miR-101a-3p 10.81 −0.14 0.53 0.67 1.59
168777 mmu-miR-5615-5p 9.09 −0.52 0.15 0.67 1.59
27855 mmu-miR-763 10.93 −1.09 −0.42 0.67 1.59
148122 mmu-miR-669p-3p 12.47 −0.45 0.22 0.67 1.60
146187 mmu-miR-1941-3p 9.28 −0.73 −0.06 0.67 1.60
17527 mmu-miR-717 8.33 −0.62 0.06 0.68 1.60
168913 mmu-miR-5115 10.51 −0.26 0.42 0.68 1.60
42916 mmu-miR-471-5p 8.73 −0.92 −0.24 0.68 1.61
148668 mmu-miR-378a-3p 11.24 0.01 0.69 0.68 1.61
148655 mmu-miR-3471 7.19 −0.66 0.03 0.69 1.61
148553 mmu-miR-1948-5p 7.73 −0.77 −0.08 0.69 1.62
148158 mghv-miR-M1-5-3p 8.84 −1.14 −0.45 0.69 1.62
42723 mmu-miR-195a-3p 9.08 −0.80 −0.10 0.70 1.63
146193 mmu-miR-1957a 10.63 −0.89 −0.18 0.71 1.63
17904 mmu-miR-185-3p 13.39 −0.42 0.30 0.72 1.65
148426 mmu-miR-466a/miR-466b/miR-466c-3p 9.88 −0.38 0.35 0.72 1.65
46206 SNORD44 8.83 −0.69 0.03 0.72 1.65
145994 mmu-miR-1900 11.60 −0.64 0.08 0.73 1.66
148020 mmu-miR-3078-3p 9.31 −0.72 0.01 0.73 1.66
148527 mmu-miR-669a-3-3p 11.99 −0.45 0.28 0.73 1.66
148212 mmu-miR-3103-3p 11.39 −0.79 −0.06 0.73 1.66
27568 mmu-miR-744-5p 11.33 −0.17 0.56 0.73 1.66
148259 mmu-miR-3070a/miR-3070b-5p 8.45 −1.05 −0.31 0.75 1.68
10952 mmu-miR-146a-5p 9.53 −0.33 0.42 0.75 1.68
42587 mmu-miR-881-5p 10.63 −0.59 0.16 0.75 1.68
148090 mmu-miR-495-5p 9.72 −0.73 0.02 0.75 1.68
148180 mmu-miR-669e-3p 9.66 −0.41 0.35 0.76 1.69
148244 mmu-miR-3098-3p 11.19 −0.91 −0.15 0.76 1.69
146021 mmu-miR-1935 11.52 −0.57 0.19 0.76 1.70
42694 mmu-miR-485-3p 9.82 −1.02 −0.25 0.77 1.70
6880 mmu-miR-297a-5p 9.37 −0.50 0.27 0.77 1.71
46979 mmu-miR-669h-3p 7.91 −0.53 0.24 0.77 1.71
11221 mmu-miR-300-3p 8.63 −0.65 0.13 0.77 1.71
29872 mmu-miR-340-5p 10.63 −1.06 −0.28 0.77 1.71
147366 mmu-miR-320-5p 9.36 −0.89 −0.11 0.77 1.71
146125 mmu-miR-1903 9.84 −0.83 −0.05 0.78 1.72
169127 mmu-miR-101a/miR-101c 9.94 −0.39 0.40 0.79 1.73
17537 mghv-miR-M1-3-3p 10.44 −0.71 0.08 0.79 1.73
168694 mmu-miR-5616-5p 9.74 −0.76 0.03 0.79 1.73
146163 mmu-miR-224-3p 9.99 −1.16 −0.37 0.80 1.74
42576 mmu-miR-342-5p 7.38 −0.83 −0.03 0.80 1.74
42861 mmu-miR-466d-3p 9.66 −0.42 0.38 0.81 1.75
42518 mmu-miR-465b-5p 11.44 −1.09 −0.28 0.81 1.75
46807 mmu-miR-466f-3p 12.19 −0.54 0.28 0.81 1.76
148533 mmu-miR-1943-3p 9.65 −0.88 −0.06 0.81 1.76
148535 mmu-miR-3097-5p 9.64 −0.75 0.07 0.82 1.76
46485 mmu-miR-669f-3p 11.96 −0.59 0.23 0.82 1.76
146055 mmu-miR-1954 10.72 −0.93 −0.11 0.82 1.76
148567 mmu-miR-1249-5p 7.87 −1.12 −0.30 0.82 1.76
146050 mmu-miR-669n 13.21 −0.67 0.15 0.82 1.76
42978 mmu-miR-466a/miR-466e-3p 8.12 −0.44 0.38 0.82 1.76
46976 mmu-miR-467g 11.59 −0.50 0.32 0.82 1.77
168651 mmu-miR-466q 11.49 −0.59 0.24 0.83 1.78
148184 mmu-miR-466m-3p 8.04 −0.58 0.26 0.84 1.79
46374 mmu-miR-466i-3p 10.39 −0.57 0.27 0.84 1.79
146097 mmu-miR-1934-5p 10.50 −1.31 −0.47 0.84 1.79
46978 mmu-miR-669i 8.29 −0.47 0.38 0.85 1.80
10925 mmu-miR-10b-5p 9.58 −0.62 0.23 0.85 1.80
146054 mmu-miR-1952 11.76 −1.19 −0.34 0.85 1.81
42703 mmu-miR-490-3p 10.59 −1.20 −0.35 0.86 1.81
17388 mmu-miR-669a-5p/mmu-miR-669p-5p 10.28 −0.66 0.20 0.86 1.82
168771 mmu-miR-5624-3p 10.06 −0.67 0.19 0.86 1.82
147953 mmu-miR-491-5p 7.66 −0.91 −0.05 0.86 1.82
146030 mmu-miR-2183 10.40 −1.09 −0.22 0.87 1.83
10995 mmu-miR-199a-3p/mmu-miR-199b-3p 10.66 −0.95 −0.08 0.87 1.83
148608 mmu-miR-551b-5p 10.23 −1.30 −0.42 0.88 1.85
168835 mmu-miR-5621-5p 7.98 −1.06 −0.17 0.89 1.85
148647 mmu-miR-3470b 10.85 −0.95 −0.05 0.90 1.86
42895 mmu-miR-881-3p 9.22 −0.84 0.06 0.90 1.87
146221 mmu-miR-669c-5p 13.66 −0.77 0.13 0.90 1.87
46453 mmu-miR-466f-5p 10.81 −0.73 0.19 0.92 1.89
42706 mmu-miR-325-3p 10.87 −1.30 −0.38 0.92 1.90
16528 mmu-miR-706 14.07 −1.02 −0.09 0.93 1.90
146081 mmu-miR-1929-5p 10.58 −0.74 0.20 0.94 1.91
148248 mmu-miR-344e-3p 8.33 −1.06 −0.12 0.94 1.92
42752 mmu-miR-872-3p 11.41 −1.50 −0.56 0.94 1.92
45985 mmu-miR-546 7.99 −1.00 −0.06 0.94 1.92
148631 mmu-miR-466j 10.56 −0.75 0.21 0.96 1.95
148378 mmu-miR-511-3p 8.17 −0.58 0.38 0.97 1.95
148068 mmu-miR-758-5p 10.64 −0.89 0.08 0.97 1.96
46734 mmu-miR-467h 10.43 −0.76 0.21 0.97 1.96
148636 mmu-miR-466f 13.10 −0.90 0.09 0.98 1.97
148325 mmu-miR-1981-3p 10.17 −1.25 −0.26 0.99 1.99
148490 mmu-miR-1224-3p 10.43 −1.25 −0.26 0.99 1.99
169364 mmu-miR-3572-3p 10.78 −1.13 −0.13 1.00 2.00
42945 mmu-miR-297c-5p 10.30 −0.79 0.22 1.00 2.00
168981 mmu-miR-378b 10.91 −0.37 0.63 1.00 2.01
148267 mmu-miR-3082-5p 13.72 −1.07 −0.04 1.02 2.03
11254 mmu-miR-468-3p 10.80 −0.95 0.08 1.03 2.04
11041 mmu-miR-29c-3p 10.29 −0.59 0.45 1.04 2.05
42606 mmu-miR-330-3p 9.34 −1.07 −0.02 1.04 2.06
169058 mmu-miR-1231-3p 9.02 −1.09 −0.04 1.06 2.08
148521 mmu-miR-466m-5p/mmu-miR-669m-5p 10.41 −0.91 0.16 1.07 2.10
27740 mmu-miR-574-5p 12.31 −0.91 0.17 1.08 2.12
145677 mmu-miR-139-5p 11.11 −2.01 −0.92 1.08 2.12
148444 mghv-miR-M1-2-5p 10.19 −0.89 0.20 1.08 2.12
168826 mmu-miR-5624-5p 11.38 −1.43 −0.34 1.08 2.12
146039 mmu-miR-669o-5p 12.20 −0.88 0.24 1.12 2.17
29575 mmu-miR-32-3p 13.38 −1.06 0.06 1.12 2.18
46346 mmu-miR-669e-5p 11.60 −0.99 0.14 1.13 2.18
148249 mghv-miR-M1-6-5p 12.12 −1.08 0.05 1.13 2.18
148403 mmu-miR-3065-3p 9.41 −0.49 0.64 1.13 2.19
148690 mmu-miR-466d-5p 12.57 −1.05 0.08 1.13 2.19
42894 mmu-miR-466e-5p 11.78 −0.99 0.15 1.13 2.19
169153 mmu-miR-5116 13.65 −1.25 −0.11 1.14 2.21
42530 mmu-let-7a-2-3p 10.14 −1.44 −0.30 1.14 2.21
148354 mmu-miR-466a-5p 11.40 −1.00 0.15 1.15 2.22
46310 mmu-miR-1187 11.55 −0.95 0.20 1.15 2.22
148433 mmu-miR-466i-5p 14.06 −1.22 −0.05 1.17 2.25
148570 mmu-miR-466n-5p 11.25 −1.01 0.17 1.19 2.28
146002 mmu-miR-669l-5p 12.05 −1.05 0.18 1.22 2.33
42803 mmu-miR-466c-5p 12.03 −1.10 0.13 1.23 2.35
147994 mmu-miR-669d-5p 12.46 −1.15 0.09 1.24 2.36
169024 mmu-miR-3960 10.80 −0.80 0.45 1.25 2.37
42847 mmu-miR-497-5p 7.82 −1.07 0.18 1.25 2.38
46381 mmu-miR-1298-5p 8.38 −0.77 0.48 1.25 2.38
148034 mmu-miR-669f-5p 12.47 −1.16 0.11 1.26 2.40
148339 mmu-miR-665-5p 11.48 −1.32 −0.06 1.27 2.41
46306 mmu-miR-466a-5p/mmu-miR-466p-5p 12.43 −1.12 0.15 1.27 2.41
29562 mmu-miR-199a-5p 10.89 −1.36 −0.07 1.29 2.44
148409 mmu-miR-669k-5p 12.59 −1.12 0.19 1.31 2.48
148143 mmu-miR-466b-5p/mmu-miR-466o-5p 11.83 −1.13 0.18 1.32 2.49
169291 mmu-miR-5126 9.84 −1.18 0.18 1.36 2.56
148653 mmu-miR-3474 13.12 −1.37 −0.01 1.36 2.57
42659 mmu-miR-290-3p 12.03 −1.29 0.08 1.36 2.57
42641 mmu-miR-145a-5p/mmu-miR-145b 9.12 −1.03 0.34 1.38 2.60
11205 mmu-miR-199b-5p 10.30 −1.29 0.16 1.46 2.74
148536 mmu-miR-1a-1-5p 7.62 −0.98 0.66 1.64 3.11
148279 mmu-miR-449a-3p 7.55 −1.42 0.25 1.67 3.19
42538 mmu-miR-196a-2-3p 9.41 −2.01 −0.15 1.86 3.62
11007 mmu-miR-206-3p 9.57 −1.03 0.86 1.88 3.69
13177 mmu-miR-143-3p 11.03 −1.51 0.54 2.05 4.14
42765 mmu-miR-339-3p 9.64 −1.90 0.29 2.19 4.56
17517 mmu-miR-688 11.16 −2.37 0.38 2.76 6.75
17653 mmu-miR-133a-5p 7.71 −2.06 1.03 3.09 8.50
146137 mmu-miR-133a-3p 10.30 −3.39 1.16 4.55 23.35
146160 mmu-miR-133b-3p 10.87 −3.50 1.15 4.65 25.09
10916 mmu-miR-1a-3p 11.21 −4.97 1.21 6.18 72.36
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2.4. Effect of mimic of miR-15b and an inhibitor of miR-133a on UVB-induced immune suppression of the CHS response

UVB-induced immunosuppression has been considered a key mechanism in photocarcinogenesis [21,22]. Therefore, to identify the role of miRNAs altered in UVB-induced tumors, the two miRNAs (miR-15b and miR-133a) were randomly selected for their role in immunosuppression in the CHS study. As shown in Fig. 4A and 4B, UVB exposure suppresses the CHS response of DNFB upto 86.45% (p<0.0018; bar 3) compared with the non-UVB exposed group (bar 2). Intraperitoneal injections of mimic of downregulated miR-15b (30nM) block UVB-induced immunosuppression upto 42.05% (p<0.0218; bar 4, Fig. 4A), while treatment with an inhibitor of upregulated miR-133a (20 nM) blocks UVB mediated immune suppression upto 69.89% (p<0.0041; bar 4, Fig. 4B). These observations revealed that maintenance of UVB mediated miRNAs protect mice from UVB induced immune suppression.

Figure 4.

Figure 4.

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The effect of intraperitoneal injections of mimic of miR-15b (A) and inhibitor of miR-133a (B) on UVB induced immunosuppression. The mice were treated with mimic/inhibitor 30 mins prior to UVB exposure. The data is presented as change in mean ear thickness ± S.E. n = 4, Statistical differences; *p<0.05, **p<0.01, ***p<0.001.

Discussion

Exposure to UV radiation is the principal cause of non-melanoma skin cancer, the most prevalent human cancer, and is also associated with the induction of malignant melanoma. The global incidence of both types of skin cancer (non-melanoma and melanoma) has been increasing over the past few years. Approximately 2–3 million non-melanoma and 132,000 melanoma skin cancers occur worldwide yearly. According to the skin care foundation, one in every three cancers is skin cancer diagnosed globally [23]. UV radiation is a complete carcinogen, which can initiate skin cancer followed by promotion and progression. Exposure to UV radiation of the skin causes inflammation, apoptosis, DNA damage, oxidative stress, immunosuppression, and premature aging of the skin [24,25].

Cancer formation is the combined interaction of tumor suppressors and oncogenes. Although several genes have been identified in human and animal models, the mechanism of cancer formation is yet to be determined. A recent study demonstrated that more than 50% of miRNA genes are located in cancer-associated genomic regions or fragile sites [26], suggesting that miRNAs may play a more critical role in the pathogenesis of a limited range of human cancers. Various studies have shown that miRNAs play essential roles in DNA methylation, cell proliferation, differentiation, angiogenesis, cell survival, and activation of several molecular pathways in cancers, such as miRNA-106b regulating cell survival pathways and enhancing cell proliferation and tumor of melanoma cells by targeting p21 expression [27]. Several other miRNAs, such as miRNA-17, miRNA-18, miRNA-19, miRNA-21, miRNA-29c, etc., have been reported for their roles in non-melanoma skin cancer [28,29].

In the miRNA profiling of UVB tumor tissues, we observed that the expression levels of several miRNAs were altered either upregulated or downregulated, and they may have an important role in photocarcinogenesis. When cells exhibit abnormal growth and loss of apoptosis function, it usually results in cancer formation. Recent studies indicate that miRNA regulates cell growth and apoptosis [30,31]. For example, miR-15 and miR-16 induce apoptosis by targeting anti-apoptotic gene B cell lymphoma 2 (BCl2) mRNA [32], which is a key player in many types of human cancers, including skin cancer. Our profiling demonstrated that expression levels of miR-15 and miR-16 were upregulated, suggesting that these miRNAs may have been involved in UVB-induced tumor formation through the regulation of cell growth and apoptosis. The expression of miRNA cluster miRNA-17-92 was also observed to be upregulated in UVB tumors. Recent studies reported that the expression of miRNA cluster miR-17-92 is remarkably increased in several other cancers, including lung cancer [33], by targeting two tumor suppressor genes, PTEN and RB1 [33]. PTEN promotes apoptosis through the P13K-Akt-PKB pathway [34]. In our results, we also observed that these miRNAs were upregulated in UVB-induced tumors and provided evidence for their role in photocarcinogenesis. Cancer is the manifestation of genetic and epigenetic events. Exposure to UVB radiation causes DNA hypermethylation and silenced tumor suppressor genes to promote tumor growth. Recent studies indicate that loss of miRNA-29s expression has a role in DNA methylation by targeting DNA methyltransferases and TET enzymes [35,36]. Our profiling results demonstrated that the levels of miRNA-29s were down regulated in UVB tumors.

Briefly, miRNAs expression profiling helps to identify a new range of miRNAs that regulate several biological processes and may involve in various diseases, including carcinogenesis and provides a better platform for distinguishing cancer tissues from normal tissues. Our observations suggest that miRNAs can be used as biomarkers and a powerful diagnostic tool for detecting cancers.

In conclusion, for the first time, we have shown that such an expression profiling approach is a suitable and effective solution for identifying aberrant miRNAs involved in cancer progression caused by UV radiation. The results of this miRNAs expression profiling in UVB-induced tumors will provide new insights into discovering potential biomarkers in photocarcinogenesis. Further mechanistic and external validation studies are needed for their clinical significance and role in the development of skin cancer.

4. Material and methods

4.1. Animals

SKH-1 hairless mice (6–7 weeks old) were purchased from Charles River Laboratory (Wilmington, MA). The mice were kept for at least one week in our animal resource facility before use in experiments. Mice were maintained under standard conditions of a 12-h dark/12-h light cycle, a temperature of 24 ± 2°C, and relative humidity of 50 ± 10%. The animal study was approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Alabama at Birmingham.

4.2. UVB irradiation and photocarcinogenesis protocol

The mice were exposed to UVB radiation, as described previously [37]. Briefly, the dorsal skin of SKH-1 hairless mice was exposed to UVB radiation from a band of four FS24T1 UVB lamps (Daavlin, UVA/UVB Research Irradiation Unit, Bryan, OH) equipped with a regulator for UVB dosa. Under the standard photocarcinogenesis protocol, mice were UVB irradiated (180 mJ/cm2; 3X/week) for upto 24 weeks. At the end of the study, mice from both cohorts were humanly euthanized, and samples were collected and stored at −80°C.

4.3. Tissue collection and RNA isolation

At the end of the photocarcinogenesis experiment, tumor and skin tissues were harvested after the euthanization of experimental mice. Total RNAs, including small ones, were extracted from the skin/tumor tissues using the Qiagen miRNeasy® mini kit. Briefly, a small portion of tissue (10mg) was lysed in 700μL Qiazol lysis reagent using a tissue lyzer with one 5mm stainless steel bead. The tissue lysate was transferred to a new tube with 140 μL chloroform, mixed, incubated for 2 min at room temperature, and centrifuged at 12,000 × g for 15 min at 4°C. The upper aqueous phase was separated, and 525μL of 100% ethanol was added. The contents were mixed gently, transferred into RNeasy mini spin column in a collection tube, and centrifuged at 8,000 × g for 15 sec at room temperature. The RNeasy mini spin column was rinsed with 700 μL RWT buffer and centrifuged at 8,000 × g for 15 sec at room temperature, followed by another rinse with 500 μL RPE buffer and centrifuged at 8,000 × g for 15 sec at room temperature. The rinse step with RPE buffer was repeated two times. After centrifugation, the flow-through was discarded, RNeasy mini spin column was transferred to a new collection tube, and the lid was left uncapped for 1 min to allow the column to dry. Total RNA was eluted by adding 50 μL of RNase-free water to the membrane of the RNeasy mini spin column and incubating for 1 min before centrifugation at room temperature. The RNAs, including small RNAs, were stored at −80°C until used.

4.4. miRNAs array profiling

All microRNAs array was conducted at Exiqon Services, Denmark. An Agilent 2100 Bioanalyzer profile verified the quality of the total RNA. 750 ng total RNA from both sample and reference was labeled with Hy3™ and Hy5™ fluorescent labels, respectively, using the miRCURY LNA™ microRNA Hi-Power labeling kit, Hy3™/Hy5™ (Exiqon, Denmark) following the procedure described by the manufacturer. The Hy3™ labeled samples and a Hy5™ labeled reference RNA sample was mixed pairwise and hybridized to the miRCURY LNA™ microRNA array 7th Gen (Exiqon, Denmark), which contains capture probes targeting all microRNAs for human, mouse, and rat registered in the miRBASE 18.0. The hybridization was performed according to the miRCURY LNA™ microRNA array instruction manual using a Tecan HS4800™ hybridization station (Tecan, Austria). After hybridization, the microarray slides were scanned and stored in an ozone-free environment (ozone level below 2.0 ppb) to prevent potential bleaching of the fluorescent dyes. The miRCURY LNA™ microRNA array slides were scanned using the Agilent G2565BA Microarray Scanner System (Agilent Technologies, Inc., USA), and the image analysis was carried out using the ImaGene® 9 (miRCURY LNA™ microRNA Array Analysis Software, Exiqon, Denmark). The quantified signals were normalized using the global LOWESS (Locally Weighted Scatterplot Smoothing) regression algorithm and background corrected [38]. As per the recommendations provided by Exiqon, smaller fold changes (≤1.0 fold) may tend to be relatively more affected by technical variance, and such changes could be associated with the increased risk of false-positive signals. Therefore the cut-off value was ≤1.0 fold change in our study. The data for miRNAs expression showing ≤1.0 fold change were eliminated during comparison within the groups.

4.5. Contact hypersensitivity (CHS) assay

The effect of miRNA-15b and miRNA-133a mimic/inhibitor on UVB-induced immune suppression in mice was assessed using the contact hypersensitivity model described previously [21,22]. Briefly, dorsal skin-shaved mice were exposed to UVB radiation (150 mJ/cm2) on four consecutive days. During the UVB exposure, ears were protected from UV irradiation by covering. After 24 hours of last UVB exposure, mice were sensitized with skin contact sensitizer 2, 4-dinitrofluorobenzene (DNFB) by topical application [(0.5% in 25 μl of acetone: olive oil mixture (4:1, v/v)]. After five days, CHS response was elicited by treating with 20 μl of 0.2% DNFB (ears). The thickness of ear skin was measured 24 h after the challenge using an engineer’s micrometer (Mitutoyo, Tokyo, Japan). The CHS response was calculated by comparing the ear thickness before the challenge. To determine the effect of miRNAs on UVB-induced immune suppression, mice were administered with the mimic of miRNA-15b (30nM; i.p) and an inhibitor of miRNA-133a (20nM; i.p.). The experimental mice were treated with miRNAs mimic/inhibitor daily, 30 mins before UVB exposure.

4.6. Statistical Analysis

Data were evaluated for outliers and adherence to a normal distribution using GraphPad Prism software (San Diego, CA, USA), version 8.1. Statistical significance of normally and non-normally distributed data were assessed via one-way ANOVA and Tukey’s multiple comparison test, respectively, with α = 0.05.

Funding:

This study was partially supported by the Vaikunthi Devi (VD) educational trust, Agra, India, to A.A and salary support to R.P from NIH-funded research projects (R01EY025383, R01EY012601, R01EY028858, R01EY032753, and R01EY028037 to Maria B. Grant).

Footnotes

Conflicts of Interest: The authors declare no conflict of interest.

Data Availability Statement:

The original data presented in the study are available on request from the corresponding author.

References

  • 1.de Pedro I.; Alonso-Lecue P.; Sanz-Gómez N.; Freije A.; Gandarillas A. Sublethal UV irradiation induces squamous differentiation via a p53-independent, DNA damage-mitosis checkpoint. Cell death & disease 2018, 9, 1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Hegedűs C.; Boros G.; Fidrus E.; Kis G.N.; Antal M.; Juhász T.; Janka E.A.; Jankó L.; Paragh G.; Emri G. PARP1 inhibition augments UVB-mediated mitochondrial changes—implications for UV-induced DNA repair and photocarcinogenesis. Cancers 2020, 12, 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Bernard J.J.; Gallo R.L.; Krutmann J. Photoimmunology: how ultraviolet radiation affects the immune system. Nature Reviews Immunology 2019, 19, 688–701. [DOI] [PubMed] [Google Scholar]
  • 4.Lee S.-J.; Lee K.B.; Son Y.H.; Shin J.; Lee J.-H.; Kim H.-J.; Hong A.-Y.; Bae H.W.; Kwon M.-a.; Lee W.J. Transglutaminase 2 mediates UV-induced skin inflammation by enhancing inflammatory cytokine production. Cell death & disease 2017, 8, e3148–e3148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Shen Y.; Stanislauskas M.; Li G.; Zheng D.; Liu L. Epigenetic and genetic dissections of UV-induced global gene dysregulation in skin cells through multi-omics analyses. Scientific reports 2017, 7, 1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Housman T.S.; Feldman S.R.; Williford P.M.; Fleischer A.B. Jr; Goldman N.D.; Acostamadiedo J.M.; Chen G.J. Skin cancer is among the most costly of all cancers to treat for the Medicare population. Journal of the American Academy of Dermatology 2003, 48, 425–429. [DOI] [PubMed] [Google Scholar]
  • 7.Jansson M.D.; Lund A.H. MicroRNA and cancer. Mol Oncol 2012, 6, 590–610, doi: 10.1016/j.molonc.2012.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Filipowicz W.; Bhattacharyya S.N.; Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008, 9, 102–114, doi: 10.1038/nrg2290. [DOI] [PubMed] [Google Scholar]
  • 9.Ambros V. The functions of animal microRNAs. Nature 2004, 431, 350–355. [DOI] [PubMed] [Google Scholar]
  • 10.Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. cell 2004, 116, 281–297. [DOI] [PubMed] [Google Scholar]
  • 11.Cohen A.; Burgos-Aceves M.A.; Smith Y. microRNAs downregulation in cancer is associated with guanine enrichment in the terminal loop sequences of their precursors. MicroRNA 2018, 7, 20–27. [DOI] [PubMed] [Google Scholar]
  • 12.Esquela-Kerscher A.; Slack F.J. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 2006, 6, 259–269, doi: 10.1038/nrc1840. [DOI] [PubMed] [Google Scholar]
  • 13.Lodygin D.; Tarasov V.; Epanchintsev A.; Berking C.; Knyazeva T.; Körner H.; Knyazev P.; Diebold J.; Hermeking H. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell cycle 2008, 7, 2591–2600. [DOI] [PubMed] [Google Scholar]
  • 14.Yi R.; Qin Y.; Macara I.G.; Cullen B.R. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes & development 2003, 17, 3011–3016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Lund E.; Güttinger S.; Calado A.; Dahlberg J.E.; Kutay U. Nuclear export of microRNA precursors. science 2004, 303, 95–98. [DOI] [PubMed] [Google Scholar]
  • 16.Ketting R.F.; Fischer S.E.; Bernstein E.; Sijen T.; Hannon G.J.; Plasterk R.H. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes & development 2001, 15, 2654–2659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Knight S.W.; Bass B.L. A role for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans. Science 2001, 293, 2269–2271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Pu M.; Chen J.; Tao Z.; Miao L.; Qi X.; Wang Y.; Ren J. Regulatory network of miRNA on its target: coordination between transcriptional and post-transcriptional regulation of gene expression. Cellular and Molecular Life Sciences 2019, 76, 441–451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Xing Y.; Wang Z.; Lu Z.; Xia J.; Xie Z.; Jiao M.; Liu R.; Chu Y. MicroRNAs: immune modulators in cancer immunotherapy. Immunother Adv 2021, 1, ltab006, doi: 10.1093/immadv/ltab006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Baffa R.; Fassan M.; Volinia S.; O’Hara B.; Liu C.G.; Palazzo J.P.; Gardiman M.; Rugge M.; Gomella L.G.; Croce C.M. MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland 2009, 219, 214–221. [DOI] [PubMed] [Google Scholar]
  • 21.Prasad R.; Katiyar S.K. Prostaglandin E2 Promotes UV radiation-induced immune suppression through DNA hypermethylation. Neoplasia 2013, 15, 795–804, doi: 10.1593/neo.13424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Prasad R.; Singh T.; Katiyar S.K. Honokiol inhibits ultraviolet radiation-induced immunosuppression through inhibition of ultraviolet-induced inflammation and DNA hypermethylation in mouse skin. Sci Rep 2017, 7, 1657, doi: 10.1038/s41598-017-01774-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Skin Cancer: facts and Statistics. Skin Care Foundation 2021.
  • 24.Cadet J.; Douki T. Formation of UV-induced DNA damage contributing to skin cancer development. Photochemical & Photobiological Sciences 2018, 17, 1816–1841. [DOI] [PubMed] [Google Scholar]
  • 25.Gu Y.; Han J.; Jiang C.; Zhang Y. Biomarkers, oxidative stress and autophagy in skin aging. Ageing research reviews 2020, 59, 101036. [DOI] [PubMed] [Google Scholar]
  • 26.Marquardt S.; Richter C.; Pützer B.M.; Logotheti S. MiRNAs targeting double strand DNA repair pathways lurk in genomically unstable rare fragile sites and determine cancer outcomes. Cancers 2020, 12, 876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Prasad R.; Katiyar S.K. Down-regulation of miRNA-106b inhibits growth of melanoma cells by promoting G1-phase cell cycle arrest and reactivation of p21/WAF1/Cip1 protein. Oncotarget 2014, 5, 10636–10649, doi: 10.18632/oncotarget.2527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Kansal V.; Agarwal A.; Harbour A.; Farooqi H.; Singh V.K.; Prasad R. Regular Intake of Green Tea Polyphenols Suppresses the Development of Nonmelanoma Skin Cancer through miR-29-Mediated Epigenetic Modifications. J Clin Med 2022, 11, doi: 10.3390/jcm11020398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Sand M.; Sand D.; Altmeyer P.; Bechara F.G. MicroRNA in non-melanoma skin cancer. Cancer Biomarkers 2012, 11, 253–257. [DOI] [PubMed] [Google Scholar]
  • 30.Tan J.; Jing Y.; Han L.; Zheng H.; Shen J.; Zhang L.; Yu L. MicroRNA-203 inhibits invasion and induces apoptosis of laryngeal cancer cells via targeting LASP1. Eur Rev Med Pharmacol Sci 2018, 22, 6350–6357. [DOI] [PubMed] [Google Scholar]
  • 31.Zhao W.; Geng D.; Li S.; Chen Z.; Sun M. Lnc RNA HOTAIR influences cell growth, migration, invasion, and apoptosis via the miR-20a-5p/HMGA 2 axis in breast cancer. Cancer medicine 2018, 7, 842–855. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 32.Cimmino A.; Calin G.A.; Fabbri M.; Iorio M.V.; Ferracin M.; Shimizu M.; Wojcik S.E.; Aqeilan R.I.; Zupo S.; Dono M. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences 2005, 102, 13944–13949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Zhang X.; Li Y.; Qi P.; Ma Z. Biology of MiR-17–92 cluster and its progress in lung cancer. International journal of medical sciences 2018, 15, 1443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Carnero A.; Paramio J.M. The PTEN/PI3K/AKT pathway in vivo, cancer mouse models. Frontiers in oncology 2014, 4, 252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Hu W.; Wang T.; Xu J.; Li H. MicroRNA mediates DNA methylation of target genes. Biochemical and biophysical research communications 2014, 444, 676–681. [DOI] [PubMed] [Google Scholar]
  • 36.Tan M.; Wu J.; Cai Y. Suppression of Wnt signaling by the miR-29 family is mediated by demethylation of WIF-1 in non-small-cell lung cancer. Biochemical and biophysical research communications 2013, 438, 673–679. [DOI] [PubMed] [Google Scholar]
  • 37.Vaid M.; Singh T.; Prasad R.; Katiyar S.K. Intake of high-fat diet stimulates the risk of ultraviolet radiation-induced skin tumors and malignant progression of papillomas to carcinoma in SKH-1 hairless mice. Toxicology and applied pharmacology 2014, 274, 147–155. [DOI] [PubMed] [Google Scholar]
  • 38.Ritchie M.E.; Silver J.; Oshlack A.; Holmes M.; Diyagama D.; Holloway A.; Smyth G.K. A comparison of background correction methods for two-colour microarrays. Bioinformatics 2007, 23, 2700–2707. [DOI] [PubMed] [Google Scholar]

Associated Data

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Data Availability Statement

The original data presented in the study are available on request from the corresponding author.

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