MicroRNAs are a type of eukaryotic endogenous small RNAs with a length of 18–25 nucleotides. Its main function is to regulate gene expression by binding to targeted RNAs (Beermann et al., 2016). The formation of miRNAs can be divided into two processes. First, the miRNA gene is transcribed into the initial transcription product (pri-miRNA), the pri-miRNA is recognized by the microprocessor and cut by the RNase III Drosha to form a hairpin structure called precursor miRNA (pre-miRNA), which is transferred from the nucleus to the cytoplasm under the mediation of Exportin-5 and RAN-GTP. Second, the pre-miRNA is cleaved into double-stranded miRNA under the action of RNase III Dicer. It then interacts with Argonaute to assemble the miRNA-induced silencing complex. The mature miRNA remains in the complex while the other strand is degraded (Ha and Kim, 2014). The mature miRNAs binds to targeted mRNA to perform post-transcriptional gene silencing role, thereby reducing the stability or inhibiting the translation of the target gene (Yang X. et al., 2020).

Long ncRNAs, with a length of more than 200 nucleotides, is transcribed by RNA polymerase II and involved in a variety of biological processes (Wong et al., 2018). LncRNAs exists both in the nucleus and cytoplasm, perform different functions according to its subcellular location (Kopp and Mendell, 2018; Miao et al., 2019; Li S. et al., 2020). The upstream promoter region encoding the protein interfered with the expression of downstream genes, and inhibits RNA polymerase II or recruits mediator proteins and chromatin remodeling enzymes to affect downstream gene transcription (Cho et al., 2018). LncRNA can be used as a scaffold to recruit RNA-binding proteins to form a nucleic acid-protein complex, and participate in chromatin remodeling and transcriptional regulation (Ban et al., 2020). In addition, it can also form a complementary double-strand with mRNA to interfere with the shearing of mRNAs (Romero-Barrios et al., 2018). Furthermore, lncRNAs interact with the protein bound to the 3′untranslated region (UTR) of mRNA in the cytoplasm to regulate the stability of mRNA (Sun et al., 2020). Antisense lncRNAs regulate the stability of mRNA by forming a double strand with mRNA (Liu et al., 2014). When lncRNAs is used as competing endogenous RNAs (ceRNAs), it can bind to miRNAs and prevent itself from inhibiting its targeted mRNAs (Li H. et al., 2020). Moreover, it can positively or negatively regulate protein translation, encoding micropeptides with regulatory functions, and can also regulate signaling pathways in the cytoplasm, and bind to specific proteins to change the cellular localization of proteins (Hosen et al., 2018).

Circular RNAs have a closed-loop structure and is more stable than linear RNAs (Hanahan and Weinberg, 2011; Lee et al., 2020). In recent years, many circRNAs with important functions are coming to light and researchers began to focused on the properties and functions of circRNAs (Iurca et al., 2020). CircRNAs is divided into three types: exonic circular RNA (ecRNA), circular intronic RNA (ciRNA), and exon-intron circular (EIciRNA; Guo et al., 2014). Among them, ecRNA is the most common one, which is mainly locate in the cytoplasm, while ciRNA and EIciRNA are abundant in the nucleus (Liang and Wilusz, 2014). CircRNAs have been demonstrated as endogenous competitive RNAs that bind to miRNAs to inhibit targeted mRNA expression (Su et al., 2019).

Small interfering RNAs are a kind of small double stranded RNA (dsRNA) with a length of 20–25 nucleotides, that are made from fully complementary long double-stranded RNA through dicer shearing (Leung et al., 2016). Exogenous dsRNA is cleaved by Dicer enzyme and TAR-RNA binding protein to form siRNA, then the siRNA loaded onto the Argonaute protein (AGO2) to form an RNA-induced silencing complex (RISC). RISC and targeted mRNA are partially or completely complementary paired, turning double-stranded siRNA into single-stranded siRNA. After combining with single-stranded siRNA, RISC become an active RISC. Targeting mRNA can be degraded through combining with activated RISC (Singh et al., 2018).

Piwi-interacting RNAs are small single-stranded RNAs with a length of 24–32nt. They have strong sense and antisense strand specificity, and the first nucleotide at the 5′-end is uracil-prone, while the 3′-end is modified by 2′-O-methylation. This type of end modification can prevent the degradation of mature piRNA genes. PiRNA must interact with PIWI protein form a piRNA silencing complex to play its regulatory role. Current studies (Guo et al., 2020) have shown that piRNA and PIWI abnormally expressed in gastric cancer, breast cancer, kidney cancer, colon cancer and lung cancer, and are involved in the occurrence, development and metastasis of cancers. PiRNAs could be potential prognostic and diagnostic biomarkers, and cancer treatment targets. PiRNA clusters are mainly distributed around centromeres and subtelomeres. They are transcribed into precursor piRNAs by RNA PolII, and are transported to the cytoplasm through primary processing pathways to form primary piRNAs, the pre-processed antisense piRNAs are loaded on Aub (Aub belongs to the Piwi subfamily) in the cytoplasm, and target the sense reverse transcript, resulting in the production of sense piRNA. These sense piRNAs are loaded onto Argonaute 3 (AGO3), and process the precursor antisense piRNA into mature piRNA. This amplification cycle continues with the continuous expression of Aub and AGO3, thereby causing a large amount of piRNA in the cell to be amplified. This phenomenon is called the “Ping-Pong” cycle (Soleimani et al., 2020). PiRNA mainly binds with PIWI or AGO3 protein, a member of the PIWI subfamily, to maintain genome stability by silencing transposable elements and regulating coding mRNA (Ng et al., 2016).

Small nuclear RNAs are a class of 50–200 nucleotides small RNAs exist in the nucleus. They are the main components of eukaryotic RNA spliceosomes. SnRNA is rich in uracil and usually numbered U1–U7. All snRNAs (except U6) have a 2,2,7-trimethylated 5′-guanosine cap (Bohnsack and Sloan, 2018). In addition to regulating the correct expression of histone mRNA and the production of rRNA, it is involved in the formation of snRNAs complexes with proteins to catalyze the splicing of precursor mRNA (Guiro and Murphy, 2017).

Small nucleolar RNAs, with a length of 60–300 nucleotides located in the nucleolus, are divided into box C/D snoRNAs and box H/ACA snoRNAs. Box C/D snoRNAs mainly mediate 2′-O-methylation at specific sites of rRNA, box H/ACA snoRNA mainly mediate the pseudo uridylation of rRNA specific sites. Both can combine with ribonucleoprotein to play a key role in rRNA processing, participate in the splicing process of rRNA and other small RNA genes (Gong et al., 2017).

MicroRNAs play an important role in various biological processes, and their roles in the pathogenesis of diseases have been observed (Jia et al., 2016). Studies have shown that miRNAs, such as miR-21, miR-106a, miR-126, miR-155, miR-182, miR-210, and miR-424, are important factors that regulate tumor angiogenesis (Huang and Chu, 2014; Jing et al., 2017; Alhasan, 2019; Sun et al., 2019; Wu et al., 2019). MiR-21, miR-126 (Du et al., 2014; Alhasan, 2019), and miR-93 (Fang et al., 2011, 2012; Fabbri et al., 2015; Liang et al., 2017; Ashrafizadeh et al., 2020) enhance the expression of HIF-1 and VEGF through targeting PTEN and inhibiting the expression of angiogenesis inhibitor thrombospondin-1 (THBS1). MiRNAs can combine with lncRNAs, such as MALAT1, to inhibit large tumor suppressor 2 (LATS2) to regulate the growth, invasion and metastasis of tumor cells. The common microRNAs that regulate tumor angiogenesis are shown in Table 1.

Abnormal expression of lncRNAs has been observed in many human cancers, and their role as tumor suppressors or oncogenes is associated with the staging and grading of tumors (Bhan et al., 2017). Different lncRNAs play different roles in tumor regulation. LncRNAs such as HOTAIR (Li et al., 2014; Yu and Li, 2015; Fu et al., 2016; Zhou et al., 2020), MALAT1, ANRIL and SRA are up-regulated in tumors and play the role of oncogenes, while MEG3, GASS and LncRNA-p21 are down-regulated in tumors and play a role of tumor suppressors. H19 (Conigliaro et al., 2015; Jia et al., 2016; Jiang et al., 2016; Lv et al., 2017; Yuan et al., 2019; Liu Z.Z. et al., 2020) plays both oncogene and suppressor roles in tumors. LncRNA H19, HOTAIR, and MVIH (Yuan et al., 2012; Lei et al., 2016; Wang Y. et al., 2020) mainly regulate the proliferation, migration, invasion and angiogenesis of tumor cells by regulating VEGF, VASH2, and miR138/HIF1α axis. LncRNAs that regulate tumor angiogenesis are shown in Table 2.

CircRNAs act as signaling molecules in regulating tumor growth, angiogenesis, invasion, metastasis, and chemotherapeutic sensitivity. In addition, circulating exosome circRNAs can affect tumor progression and malignant characteristics. CircRNA has great value in tumor diagnosis and prognosis, and is a promising non-invasive biomarker (Wang M. et al., 2020). Circ-ATXN1 (Liu X. et al., 2020), circ-SHKBP1 (Xie et al., 2020), and circ-001971 (Chen et al., 2020) mainly regulate VEGF through sponging miRNAs and activate PI3K/AKT signaling pathway to promote tumor cell proliferation, migration and angiogenesis. Common circRNAs that regulate tumor angiogenesis are shown in Table 3.

Previous studies have shown that (Liu X. et al., 2020) angiogenesis plays an important role in the occurrence and development in gliomas. The expression of circ-ATXN1 significantly enhances the cell viability, migration and tube formation in GECs. Circ-ATXN1 functionally targets miR-526b-3p in the RISC and affects the angiogenesis of vascular endothelial cells by negatively regulating the expression of MMP2/VEGFA. Xie et al. (2020) found that circ-SHKBP1 is expressed in gastric cancer tissues and serum of patients. As a sponge molecule, circ-SHKBP1 can adsorb miR-582-3p to increase the expression of HUR, enhance the stability of VEGF mRNA, and promote angiogenesis of gastric cancer cells. Circ-001971 acts as a ceRNA by relieving miR-29c-3p-induced VEGFA inhibition, thereby aggravating the proliferation, invasion and angiogenesis of colorectal cancer (Chen et al., 2020). Zheng et al. (2020) found that the expression of circ-0056618 increased in colorectal cancer tissues and colorectal cancer cell lines. Circ-0056618 acts as a sponge molecule to adsorb miR-206 and eliminate the inhibitory effect of miR-206, thereby upregulating CXCR4 and VEGF-A in colorectal cancer. Circ-PRRC2A acts as a sponge molecule to adsorb miR-514a-5p and miR-6776-5p to prevent the degradation of the mRNA of tissue-specific oncogene TRPM3, promoting angiogenesis and tumor metastasis (Li W. et al., 2020). CircRNA-MYLK can directly bind to miR-29a and reduce the inhibition of VEGFA, thereby activating the VEGFA/VEGFR2 signaling pathway, ectopic expression of circRNA-MYLK promotes the proliferation, migration, tubular formation and cytoskeleton rearrangement of HUVEC (Zhong et al., 2017). Hsa-circ-0000515 is up-regulated in breast cancer tissues. Hsa-circ-0000515 binds to miR-296-5p to prevent it from inhibiting CXCL10 expression, promotes cell cycle progression, cell proliferation and invasion of breast cancer cells, and increases the potential of cancer cells to promote angiogenesis (Cai et al., 2021). He et al. (2019) showed that circ-DICER1 acts as a molecular sponge to adsorb miR-103a-3p and miR-382-5p, and weaken its negative regulatory effect on ZIC4 in GECs. ZIC4 up-regulates the expression of its downstream target Hsp90β, and Hsp90 activates the PI3K/AKT signaling pathway and promotes cell viability, migration and tubular cell formation.

Small Interfering RNAs silences targeted genes to inhibit angiogenesis of cancer cells and tumor growth. In vivo, siRNAs can significantly influence tumor angiogenesis by regulating related genes and pathways. Common siRNAs that regulate tumor angiogenesis are shown in Table 4.

Yang F. et al. (2020) used polymer micelles as a carrier to deliver triptolide and siRNA to retinoblastoma (RB) cells. The micelle carrier loaded with triptorelin and HIF-1 siRNA showed effective cell internalization, inhibited the expression of HIF-1α and VEGF in RB cells, leading to inhibition of the HIF-1α/VEGF/VEGFR signaling pathway, and the proliferation, migration, and invasion of vascular endothelial cells. Bastaki et al. (2021) generated trimethyl chitosan and thiolated chitosan nanoparticles (NPs) conjugated with HIV-1-derived TAT peptide and HA (hyaluronic acid). These NPs exhibited prominent physicochemical characteristics, notable siRNA encapsulation, serum stability, non-toxicity, controlled siRNA release, and extensive cellular uptake by cancer cells. The siRNAs silenced targeted genes, immune checkpoint molecule programmed cell death ligand 1 and oncogene transcription factor STAT3, which significantly inhibits the proliferation, migration and angiogenesis of cancer cells, inhibits tumor growth in the body. Shan et al. (2020) found that chitosan magnetic nanoparticles (CMNPs) carrying Ang-2 small interfering RNA plasmids have inhibitory effects on malignant melanoma, and can significantly inhibit the growth of melanoma. In vivo, Ang2-CMNP significantly inhibits tumor angiogenesis and promotes cell apoptosis by adjusting the ratio of Bax/Bcl-2 and increasing the expression of caspase-3. Shobaki et al. (2020) using optimized load CL4H6-LNP (CL4H6 is a novel, pH-sensitive cationic lipid, LNP is a lipid nanoparticle) siRNA targeting TAMs, and anti-tumor response is obtained in the same tumor model. The anti-tumor therapeutic response was obtained through the silencing of STAT3 and HIF-1α, which resulted in an increase in the level of infiltrated macrophage (CD11b⁺ cells) into the tumor microenvironment as well as a tendency to increase the concentration of M1 macrophages (CD169⁺ cells). The treatment also resulted in reversing the pro-tumorous functions of TAMs -mainly angiogenesis and tumor cell activation.

Although the association of other ncRNAs such as piRNAs, snRNAs and snoRNAs with tumor angiogenesis has not been reported, they also play important roles in the development of tumors. Common other ncRNAs affect the occurrence and development of tumor are shown in Table 5.

Both PIWI protein and piRNA are mainly expressed in germ-line cells and abnormally expressed in a variety of cancer cells. Weng et al. (2018) found that piR-1245 is overexpressed in colorectal cancer, and the overall survival of patients with piR-1245 overexpression is significantly shortened. PiR-1245 acts as an oncogene and promotes tumor development by targeting tumor suppressor genes such as ATF3, BTG1, DUSP1, FAS, NFKBIA, UPP1, SESN2, TP53INP1, and MDX1.

U1 snRNA, as one of the most abundant ncRNAs in human cells, has a high recurring A > C somatic mutation at the third base (Shuai et al., 2019). This mutation changes the splicing pattern of multiple genes, including known cancer driver factors, accounting for the mechanism of abnormal snRNA in cancers.

Siprashvili et al. (2016) compared 5,473 pairs of tumor-normal genome pairs. They found that in 12 common cancers, 10–40% of snoRNA loci were deleted, the deletion of snoRNAs promoted tumorigenesis, but the mechanism is still unknown.

Piwi-interacting RNAs, snRNAs, and snoRNAs are abnormally expressed in a variety of cancer cells, and play important roles in the occurrence and development of cancers. However, their relationship with tumor angiogenesis has not yet been reported. Because tumor angiogenesis plays an indispensable role in the development of tumors, the relationship between these ncRNAs and tumor angiogenesis warrants further explored.