Long Non-coding RNA Small Nucleolar RNA Host Gene 14, a Promising Biomarker and Therapeutic Target in Malignancy

Small nucleolar RNA host gene 14 (SNHG14) is a long non-coding RNA found to be overexpressed in various types of cancers. Moreover, the expression level of SNHG14 was closely associated with multiple clinicopathological characteristics such as prognosis, tumor differentiation, TNM stage, and lymph node metastasis. Functionally, gain- and loss-of-function of SNHG14 revealed that overexpressed SNHG14 promoted cancer cell viability, invasion, and migration, whereas its down-regulation produced the opposite effect. Mechanistically, regulating its target gene expression by sponging distinct miRNAs might be the major mechanism underlying the oncogenic functions of SNHG14. Thus, SNHG14 might be a promising prognostic biomarker and therapeutic target for cancers. In this review, we discuss the expression profile, biological function, and molecular mechanisms of SNHG14 in cancers to provide a molecular basis for the clinical utility of SNHG14 in the future.

LncRNA small nucleolar RNA host gene 14 (SNHG14) is a new lncRNA located on chromosome 15q11.2 in humans. It has played an essential role in promoting inflammation microglia activation (Qi et al., 2017;Zhong et al., 2019;Jiang et al., 2021), sepsis-induced acute kidney injury (Shi et al., 2021), and LPSinduced acute kidney injury . In addition to its function in tumorigenesis and progression, SNHG14 was found to function as a competing endogenous RNA for microRNAs-382-5p (miR-382-5p) to regulate SPIN1 expression in non-small cell lung cancer . Tang and Yang (2020) reported that SNHG14 binds to miR-656-3p using dualluciferase reporter assay in hepatocellular carcinoma (HCC). Xie et al. (2020) found that SNHG14 promoted pancreatic ductal adenocarcinoma progression by regulating E-cadherin expression by interacting with EZH2. Collectively, the regulatory mechanisms of SNHG14 are highly complicated and unclear.
In this study, we summarize the latest evidence of SNHG14 in human cancers, especially its abnormal expression, biological functions, and molecular mechanisms, and discuss the potential clinical value of SNHG14 as a novel method for cancer diagnosis, prognosis, and treatment.

CLINICAL RELEVANCE OF SMALL NUCLEOLAR RNA HOST GENE 14 IN CANCERS
Tissue-specific expression patterns indicate that lncRNAs might be served as potential biomarkers and provide a rationale to target them clinically (Statello et al., 2021;Winkle et al., 2021). To explore the role of SNHG14 in cancer, some research groups have studied the expression profile, roles, and clinical significance of SNHG14 in various types of cancers (Table 1). Feng et al. (2021) reported that 37 of 62 of SNHG14 expressions were significantly increased in bladder cancer tissues than in normal control tissues. Another study found this lncRNA was overexpressed in HCC tissues and cell lines . Up-regulation of SNHG14 in tumor tissues was also found in multiple cancer types, such as NSCLC (Zhang et al., 2019d), HCC (Pu et al., 2019), osteosarcoma (Hou and Mao, 2020), ovarian cancer , glioma (Lu et al., 2020), prostate cancer , breast cancer (Dong et al., 2018a), clear cell renal cell carcinoma (Liu et al., 2017), retinoblastoma , acute myeloid leukemia (Wang et al., 2021a), pancreatic cancer (Zhang et al., 2019b), colorectal cancer (Han et al., 2020), cervical cancer (Ji et al., 2019), and endometrial cancer . Notably, the expression of SNHG14 in glioma (Wang Q. et al., 2018), colorectal cancer , and endometrial carcinoma (Zhang K. et al., 2020) was controversial. We suggest that large sample size and cross-regional or even cross-national multicenter large sample verification may provide better evidence for the conclusion. We believe that the existing studies are contradictory and may be affected by various factors such as detection methods, sensitivity and experimental conditions These seemingly contradictory conclusions suggest that further research is needed to this regard. Importantly, the expression level of SNHG14 has been demonstrated correlated with prognosis in patients with NSCLC (Zhang et al., 2019d), HCC , ovarian cancer , retinoblastoma , pancreatic ductal adenocarcinoma (Xie et al., 2020), colorectal cancer (Pei et al., 2019), cervical cancer (Ji et al., 2019), and endometrial cancer . Furthermore, some researchers discovered that highly expressed SNHG14 was positively correlated with large tumor size, advanced TNM stage, distant metastasis and poor tumor differentiation in bladder cancer (Feng et al., 2021), NSCLC (Zhang et al., 2019d), HCC (Liao et al., 2021), prostate cancer , retinoblastoma , pancreatic cancer (Deng et al., 2019), and cervical cancer (Ji et al., 2019). The results indicate that SNHG14 can become a prognostic indicator of cancers.
ROC curves analysis showed that the sensitivity of SNHG14 in HCC was 98.5% and the optimal cutoff value of SNHG14 was 1.22 (Tang and Yang, 2020). In bladder cancer, the survival curve analysis of SNHG14 showed that the area under the curve was 0.842 and the cutoff value was 2.714, indicating the diagnostic potential of SNHG14 . Zhao et al. (2020) also confirmed the diagnosis efficiency of SNGH14 in ovarian cancer.
Generally, the aforementioned results suggest that SNHG14 plays an oncogenic role in various types of cancer, and it may serve as a new biomarker for cancer diagnosis and prognosis, although further investigation is required for clinical application.

BIOLOGY FUNCTION AND THE MOLECULAR MECHANISM OF SMALL NUCLEOLAR RNA HOST GENE 14 IN VARIOUS CANCERS
Emerging evidence revealed the expression of SNHG14 in tumor cell lines and the effect of knockdown or overexpression of this lncRNA on tumor cell malignant characteristics such as proliferation, invasion, migration, apoptosis, and drug resistance. The regulatory mechanisms of SNGH14 are complex in distinct types of cancers, even in one cancer. The major mechanism underlying the tumor-promoting function of SNHG14 is to regulate target genes via competing with miRNAs ( Table 2). In the following sections, we focus on the function of SNHG14 in various cancers.

Bladder Cancer
Bladder cancer is one of the most common cancers and has high mortality worldwide (DeGeorge et al., 2017;Lenis et al., 2020). Recently, lncRNAs were found to be closely correlated with bladder occurrence and development (Martens-Uzunova et al., 2014;Cao et al., 2020;Li et al., 2020). However, the molecular mechanism of lncRNAs in the pathogenesis of bladder cancer is still unclear. The expression level of SNHG14 in bladder cancer cell lines (T24, 5637, UMUC-3, and EJ) was higher than in normal bladder epithelial cells SV-HCV-1 Feng et al., 2021). Feng et al. (2021) reported that knockdown of lncRNA in T24 cells suppressed cell proliferation, migration, and invasion, while facilitating cell apoptosis, overexpression this lncRNA shows an opposite effect. The results of bioinformatic analysis and luciferase reporter assay demonstrated that SNHG14 functions as a cancer-promoting gene by targeting miR-211-3p to regulate ESM1 expression (Feng et al., 2021). In other studies, the overexpression of SNHG14 was found to accelerate the proliferative potential by sponging miR-150-5p to degrade VAMP2 expression . The aforementioned results suggest that SNHG14 is a potential therapeutic target for bladder cancer.

Non-small Cell Lung Cancer
Lung cancer is the most commonly diagnosed cancer, with approximately 1.8 million cancer-related deaths worldwide in 2018 (Bray et al., 2018). NSCLC accounts for 85% of all lung cancer cases (Ginn et al., 2020). The 5-year survival rate for patients with advanced-stage NSCLC remains approximately 14% (Ko et al., 2018). This highlights a need to develop new ways to tackle the disease. Zhang et al. (2019d) reported that SNHG14 expression was markedly higher in NSCLC cell lines (including A549, NCI-H1975, NCI-H1299, and SK-MES-1) than normal 16HBGE cells, and overexpression of SNHG14 promoted cell proliferation by targeting miR-340. A recent study found that overexpression of SNHG14 facilitates NSCLC cell proliferation, invasion, and migration by regulating G6PD expression by sponging miR-206 . Similarly, Chen et al. (2020) demonstrated that SNHG14 accelerated NSCLC progression via the miR-382-5P/SPIN1 axis. Additionally, SNHG14 was reported to influence NSCLC cisplatin resistance by modulating the HMGB1 expression through targeting miR-34a (Jiao et al., 2019). Specifically, in this research, the expression of SNHG14 was remarkably high in cisplatin-resistant NSCLC cell lines (A549 and H1299) compared with that in the human bronchial epithelioid cell line (16HBE). SNHG14 silencing or overexpression miR-34a promoted cell sensitivity to cisplatin (Jiao et al., 2019). SNHG14 was also revealed to regulate the cisplatin resistance through the miR-133a/HOXB13 pathway (Xu L. et al., 2020). Wu et al. (2019)    Not studied Zhang K. et al., 2020 Frontiers in Cell and Developmental Biology | www.frontiersin.org FIGURE 1 | SNHG14 enhances non-small cell lung cancer cell proliferation, invasion, and migration and inhibits cell apoptosis by regulating target genes through sponging miRNAs.
found that SNHG14 expression was increased in gefitinibresistant cells, and overexpression of SNGH14 promoted gefitinib resistance by facilitating cell growth and restraining cell apoptosis through interacting with miR-206-3P. Briefly, SNHG14 plays a vital role in promoting NSCLC cell proliferation, migration, invasion, and chemoresistance and inhibiting cell apoptosis by regulating targets by sponging different miRNAs (Figure 1). SNHG14 is expected to provide a novel strategy for NSCLC treatment.

Hepatocellular Carcinoma
HCC is one of the most commonly diagnosed cancers and ranks the fourth leading cause of cancer-related deaths worldwide in 2018 (Bray et al., 2018). Dysregulated lncRNAs have been found closely related to tumorigenesis, prognosis, and diagnosis (Abbastabar et al., 2018;Wong et al., 2018;Pan et al., 2019). SNHG14 was found highly expressed in HCC cell lines compared with that in the normal cell line. As for biological function, the overexpression of this lncRNA accelerated cell proliferation, invasion, and migration and suppressed cell apoptosis. Conversely, knockdown of SNHG14 could cause the exact opposite effects on HCC cells (Pu et al., 2019;Tang and Yang, 2020;Xu X. et al., 2020;Liao et al., 2021). Mechanistic investigations demonstrated that SNHG14 functions as a competing endogenous RNA and sponged miRNAs, such as miR-4673, miR-217-5p, miR-656-3p, and miR-876-5p (Pu et al., 2019;Tang and Yang, 2020;Liao et al., 2021). Thus, activating downstream gene expression, such as, SOCS1, SIRT5, and SSR2 (Figure 2; Pu et al., 2019;Tang and Yang, 2020;Liao et al., 2021). Another research group reported that SNHG14 contributed to tumor cell malignant cells by increasing poly(A) binding protein cytoplasmic 1 (PABPC1) expression through H3K27 acetylation. In this study, gain-and loss-offunction experiments also revealed that the phosphatase and tensin homolog (PTEN) signaling pathway was involved in SNHG14/PABPC1-mediated regulation of tumorigenesis in vitro and in vivo (Figure 2; . Accordingly, SNHG14 has an oncogenic role and might be a potential therapeutic target in HCC.

Ovarian Cancer
The SNHG14 expression level was enormously high in ovarian cancer cells compared with the control cell line Zhao and Huang, 2019). Zhao et al. discovered that overexpressed SNHG14 could accelerate cell proliferation and cell cycle. Dual-luciferase assay indicated that SNHG14 could directly bind to miR-125a-5p, and overexpression of miR-125a-5p reversed the effect of promoting tumor of SNHG14 on ovarian cancer cells . SNHG14 was also found to promote ovarian cancer metastasis by regulating DGCR8 expression . Although the underlying molecular mechanism and signaling pathway need to be further studied, the aforementioned evidence proved novel clues for the treatment of ovarian cancer.

Breast Cancer
Breast cancer with overexpression of human epidermal growth factor receptor 2 (HER2) accounted for 20-30% of all breast cancers and had poorer prognosis (Vu and Claret, 2012;Robidoux et al., 2013). Trastuzumab is an HER2 inhibitor that is used for initial and advanced treatment. However, trastuzumab resistance has been a significant obstacle to improving the outcome of patients (Wolff et al., 2007;Narayan et al., 2009). To explore the contributions of lncRNAs in trastuzumab resistance and progression of breast cancer, Dong et al. (2018b) cultured human breast cancer cell lines SKBR-3 and BT474 and trastuzumab-resistant SKBR-3/Tr and BT474/Tr cells to identify the role of SNHG14 in breast cancer progression and drug resistance. Functional experimentation demonstrated that knockdown of SNHG14 restrain cell proliferation, invasion, trastuzumab resistance, and the overexpression of SNHG14 abolished this effect. Consistent with this effect, Dong et al. (2018a) also found SNHG14 promoted trastuzumab chemoresistance in breast cancer. Thus, SNHG14 may serve as a promising target for patients with HER2positive breast cancer.

Colorectal Cancer
In colorectal cancer, Di et al. (2019) found that the level of SNHG14 was markedly upregulated in colorectal cancer cell lines compared with that in the control colonic cell line (Wang et al., 2021b). Overexpression of SNHG14 promoted colorectal cancer cell proliferation, invasion, and migration and epithelialmesenchymal transition in vitro and enhanced tumor growth and distant metastasis in vivo (Di et al., 2019;Pei et al., 2019;Ye et al., 2019;Han et al., 2020). Furthermore, mechanistic investigations demonstrated that SNHG14 facilitates colorectal cancer progression by targeting EZH2-regulated EPHA7 and absorbing miR-186-5p (Di et al., 2019). Pei et al. (2019) reported that SNHG14 could serve as an oncogene by regulating the miR-944/KRAS axis via the PI3K/AKT signaling pathway. SNHG14 was also found to regulate colorectal cancer progression via the miR-32-5p/SKIL and miR-186/ATG14 axes (Ye et al., 2019;Han et al., 2020). In contrast to the aforementioned study, a single study reported that SNHG14 was significantly down-regulated in colorectal cancer cell lines compared with that in a normal cell line and SNHG14 exerts an anti-tumor effect through sponging miR-92b-3p . Thus, further studies are still needed before determining conclusions related to the function and regulatory mechanisms of SNHG14 in colorectal cancer. Lu et al. (2020) revealed that SNHG14 is involved in reprogramming glucose metabolism and tumorigenesis by interacting with RNA-binding protein Lin28A in glioma. Silencing SNHG14 inhibited glioma cell glycolysis and proliferation while enhancing apoptosis. In contrast to the aforementioned study, another study demonstrated the role of SNHG144 in the suppression of cell proliferation and invasion and promotion of apoptosis in glioma (Wang Q. et al., 2018).

Pancreatic Cancer
Pancreatic cancer a highly fatal gastrointestinal malignancy and ranks the seventh leading cause of cancer-related deaths (Luchini et al., 2016). Although the diagnosis and management of pancreatic cancer are improved, the 5-year survival rate is as low as 4% (Vincent et al., 2011;Gandhi et al., 2018). Pancreatic ductal adenocarcinoma is the most common pathological type of pancreatic cancer and lacks effective treatment (Luchini et al., 2016;Gallmeier and Gress, 2018). In recent years, growing amount of evidence shows that lncRNAs may play vital roles in the development and maintenance of pancreatic cancer FIGURE 3 | Function and molecular mechanism of SNHG14 in pancreatic cancer. (Taucher et al., 2016;Moschovis et al., 2017;Wang J. et al., 2020). Some studies have reported that SNHG14 expression was significantly higher in pancreatic cancer cells compared with that in normal cell lines, and upregulated this lncRNA enhanced cell proliferation and invasion through regulating E-cadherin expression via binding on promoters of EZH2 (Xie et al., 2020). Mechanistically, this lncRNA was also found to potentiate tumor progression through modulation of target gene annexin A2 via sponging miR-613 (Deng et al., 2019). Alternatively, Zhang et al. (2019b) reported that SNHG14 increased gemcitabine resistance to pancreatic cancer cells by increasing autophagy-related proteins (such as RAB5A and ATG4D) through interacting with miR-101. The function and molecular mechanism of SNHG14 are shown in Figure 3. Collectively, SNHG14 shows its role in the initiation, progression, and drug resistance, suggesting its potential role in tumor treatment of pancreatic cancer.

Others
Other studies on cervical cancer (Ji et al., 2019;Zhang et al., 2019c), prostate cancer , osteosarcoma (Hou and Mao, 2020), endometrial cancer , retinoblastoma , clear cell renal cell carcinoma (Liu et al., 2017), diffuse large B cell lymphoma Tian et al., 2021), and acute myeloid leukemia (Wang et al., 2021a) indicated a tumor promoter role for SNHG14 through complex molecular mechanisms. Table 2 summarizes the current results of the function, target genes, and signaling pathways in various malignancies.

CONCLUSION AND PERSPECTIVES
With the development of RNA-seq technologies, bulk lncRNAs are being identified and characterized (Jathar et al., 2017;Wang J. et al., 2018;Qian et al., 2019;Gu et al., 2021). Dysregulation in the expression of lncRNAs has been demonstrated to participate in diverse diseases, especially cancer (Poliseno et al., 2015;Peng and Croce, 2016;Kristensen et al., 2018). LncRNA SNHG14 has been found to be overexpressed in various cancer tissues and is closely associated with multiple clinicopathological characteristics such as prognosis, tumor differentiation, TNM stage, and lymph node metastasis. As a tumor promotion gene, the results of functional experiments have demonstrated that overexpression of this lncRNA could promote tumor cell proliferation, migration, invasion, and chemoresistance and inhibit cell apoptosis. The regulatory mechanism of SNHG14 is complex in distinct types of cancers. To regulate target genes via competing with miRNAs is the major mechanism underlying the tumor-promoting function of SNHG14 by regulating target genes via sponging different miRNAs, such as miR- 5590-3p, miR-152-3p, miR-193b-3p, miR-92b-3p, miR-186, miR-32, and miR-93-5p (Table 2).
As for clinical application, high expression of SNHG14 was closely correlated with poorer clinicopathological characteristics; thus, it may be served as a potential biomarker for diagnosis and prognosis. However, most of the studies lack a sufficiently large sample and might have artificial errors. The expression of SNHG14 was tested only in tissues. The expression level of SNHG14 in serum or other biological samples remains unclear and is worth investigating. Therefore, exploring the expression of SNHG14 in blood and other fluids would be beneficial to its clinical application as a diagnostic marker in the future. Additionally, although several studies have addressed the promising role of SNHG14 as a target for cancer treatment, research on SNHG14 is still in its early stages. When could targeting SNHG14 be used in clinical treatment? The main determinant is the availability of drugs (whether oligonucleotide or small molecule drugs) that manipulate SNHG14 activity and deliver them effectively to tumor cells with lasting effects. Furthermore, clarification of the functions and mechanisms of SNHG14 under physiological and pathological conditions is also necessary.

AUTHOR CONTRIBUTIONS
SS and YW wrote and reviewed the manuscript. YZ collected the references. ZD and JX reviewed the manuscript. All authors contributed to the writing and revision of the manuscript, knew the content of it, and approved its submission.