MicroRNA‐381 in human cancer: Its involvement in tumour biology and clinical applications potential

Abstract MicroRNAs (miRNAs) are small non‐coding RNAs that regulate gene expression at the post‐transcriptional level. MiRNAs are involved in the development and progression of a wide range of cancers. Among such cancer‐associated miRNAs, miR‐381 has been a major focus of research. The expression pattern and role of miR‐381 vary among different cancer types. MiR‐381 modulates various cellular behaviours in cancer, including proliferation, apoptosis, cell cycle progression, migration and invasion. MiR‐381 is also involved in angiogenesis and lymphangiogenesis, as well as in the resistance to chemotherapy and radiotherapy. MiR‐381 itself is regulated by several factors, such as long noncoding RNAs, circular RNAs and cytokines. Aberrant expression of miR‐381 in blood samples indicates that it can be used as a diagnostic marker in cancer. Tissue miR‐381 expression may serve as a prognostic factor for the clinicopathological characteristics of cancers and survival of patients. Metformin and icaritin regulate miR‐381 expression and present anticancer properties. This review comprehensively summarizes the effect of miR‐381 on tumour biological behaviours, as well as the clinical application potential of miR‐381 for the treatment of cancer.

mechanisms to highlight the potential of miR-381 as a biomarker for cancer diagnosis and a target for cancer therapy.

| Chronic myeloid leukaemia
MiR-381 expression is lower in chemoresistant Chronic myeloid leukaemia (CML) cells than in parental cells, suggesting that it acts as a tumour suppressor by interfering with chemoresistance (Table 2).
Mechanistically, miR-381 resensitizes doxorubicin-resistant and vinblastin-resistant CML cells by targeting the multidrug resistance gene 1 (MDR-1). MiR-381 downregulates the expression of Pglycoprotein (P-gp), the protein product of the MDR-1 gene, thereby inhibiting drug efflux in chemoresistant cells and leading to the intracellular accumulation of chemotherapeutic drugs. 42

| Glioma
MiR-381 is overexpressed in glioma and may function as an oncomiR (

| Non-smallcelllungcancer
The downregulation of miR-381 indicates its suppressive role in NSCLC ( apoptosis in NSCLC, respectively. Furthermore, miR-381 reverses cisplatin resistance in NSCLC. 47 In addition to its effect on the resistance to traditional chemotherapy drugs, miR-381 also affects the resistance of NSCLC to immunotherapy, such as anti-programmed

Colorectal cancer
Similar to its role in gastric cancer, miR-381 may also act as a negative regulator of Twist1 in CRC (

| Pancreatic cancer
The network of chemokines and receptors in the tumour microenvironment is complex. Chemokines interact with relevant receptors and have various biological functions in cancer. In pancreatic cancer, CXCR4 is a target of miR-381 and its expression is upregulated.
Under stimulation by its functional ligand CXCL12, CXCR4 not only promotes cell survival and proliferation but also facilitates cell motility and invasion in pancreatic cancer (Table 5). 55 The carcinostatic action of miR-381 in pancreatic cancer may also be attributed to its inhibitory effect on the expression of ever shorter telomeres pro- replication and gene transcription, which increases the tumourigenesis of HCC. 58 MiR-381 regulates the expression of LRH-1 in HCC (Table 5)

| Bladder cancer
Bladder cancer is the most common urologic malignancy, and it is associated with an unfavourable prognosis. 61 In bladder cancer, miR-381 interferes with cell cycle progression (  (Table 6). In PCa, miR-381 targets AR and downregulates its expression, thereby playing an inhibitory role in PCa. 23 In addition, downregulation of UBE2C mediated by miR-381 is responsible for reduced cell proliferation and invasion in PCa 63 (Table 6).

| Ovarian cancer
In developed countries, ovarian cancer accounts for the majority of deaths among all gynecologic malignancies. 64 MiR-381 suppresses YY-1, which decreases cell proliferation, migration and invasion in ovarian cancer. 26 MiR-381 may also act as the upstream regulator of phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) ( Table 6). MiR-381 directly targets PIK3CA and negatively regulates cell proliferation, migration and invasion in ovarian cancer. 25

| Endometrial cancer
Endometrial cancer is the sixth most common malignancy among women. 65 MiR-381plays a suppressive role in EMC (Table 6) (Table 6).

TA B L E 9 Biological role of miR-381 in other cancer types
( Table 9). The anticarcinogenic effect of miR-381 on PTC is attributed to the suppression of low-density lipoprotein receptor-related protein 6, an essential Wnt co-receptor, to activate Wnt/β-catenin signalling. 35

| Laryngeal squamous cell carcinoma
In addition to OSCC, the suppressive role of miR-381 was observed in other head-neck squamous cell carcinomas such as LSCC. In LSCC, miR-381 downregulates nuclear autoantigenic sperm protein (NASP) ( Table 9), thereby decreasing cell proliferation and reversing the EMT phenotype, which reduces cell migration and invasion in LSCC. 37

| LncRNAandCircRNA
The expression of miR-381 is regulated by various long non-coding RNAs (lncRNAs) ( Figure 1A). In osteosarcoma, lncRNA CAT104 induces the expression of ZEB1 by sponging miR-381, thereby increasing cell proliferation, migration and invasion and suppressing cell apoptosis. 68 Similar effects of lncRNA CAT104 were observed in gastric cancer. 53 The lncRNA TUG1 also functions as an endogenous suppressor of miR-381 in gastric cancer. 16 In cervical cancer, lncRNA TUG1 upregulates the expression of HOXA13 by inhibiting miR-38, thereby promoting cell proliferation and invasion. 29 In pancreatic cancer, the lncRNA DLEU1 is overexpressed and targets miR-381 to upregulate the expression of CXCR-4, thereby aggravating the progression of pancreatic cancer. 55 In addition to lncRNAs, the circular RNA (circRNA) FGFR1 is involved in the regulation of miR-381 ( Figure 1A). In NSCLC, FGFR1 serves as a sponge for miR-381 to upregulate CXCR4. The upregulation of CXCR4 by miR-381 promotes the progression of NSCLC and induces resistance to anti-PD-1-based therapy. 48

| Others
In addition to non-coding RNAs, the expression of miR-381 in cancer is regulated by several molecules ( Figure 1A). Periostin is secreted by osteoblasts and indispensable for the adhesion and extension of osteoblasts. 75 Recent studies suggest that periostin is involved in the metastatic process of human cancers. In NSCLC, periostin activates the ERK and p38 pathways, thus suppressing the expression of miR-381. 45 In breast cancer, enhancer of zeste homolog 2 is

| MiR-381asanon-invasivemarkerforcancer diagnosisandmonitoring
Aberrant expression of circulating miRNAs suggests their potential as non-invasive markers for the diagnosis of cancer. MiR-381 is upregulated in the peripheral blood of patients with glioma. 43 By Extra efforts are supposed to be devoted to the detection of miR-381 in blood samples.
In patients with osteosarcoma, miR-381 expression differs between patients with postoperative recurrence and those without. 39 The upregulation of tissue miR-381 in patients with recurrent osteosarcoma reveals the potential of miR-381 for the monitoring of cancer recurrence and metastasis.

| TheprognosticvalueofmiR-381incancer
Because of the differential expression of miR-381 in different cancer

| ThepotentialofmiR-381asatherapeutic targetincancer
In NSCLC, miR-381 serves as the target of metformin, which is a In conclusion, miR-381 is involved in a variety of cancer biological functions, suggesting its potential for cancer diagnosis, prognosis and treatment. Future efforts should be devoted to the application of miR-381-based diagnostic and therapeutic strategies in clinical practice.

DATAAVA I L A B I L I T YS TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.