Aberrant expression of MiR-148/152 family has been observed in tumor [
7,
21] and nontumor [
22] diseases. Many studies have identified that MiR-148/152 family members potentially acted as oncogenes and tumor suppressors. Moreover, the growing evidence has demonstrated that miR-148/152 family members also played important roles in some nontumor diseases, such as IgA nephropathy [
22], type 1 diabetes [
23], atherosclerotic lesions [
24], chronic fatigue syndrome/myalgic encephalomyelitis [
25].
Upregulation of miR-148/152 family
MiR-148/152 family members are upregulated in many diseases. Huang et al. reported that six miRNAs including miR-148a were significantly upregulated in the plasma of multiple myeloma (MM) and high levels of miR-148a were related to shorter relapse-free survival times [
21]. Also in plasma, Cuk et al. noted that miR-148b was significantly upregulated in breast cancer patients [
26]. Moreover, Yuan et al. reported that miR-148a was upregulated in hepatitis B cells associated with hepatocellular carcinoma (HCC) [
27]. Furthermore, Gokhale et al. found miR-148a, as one of abnormal expressed miRNAs, was overexpressed in the WNT signaling-associated medulloblastomas [
28]. Therefore, miR-148a and miR-148b might be significant biomarkers in these cancer patients and might provide an early easy detection method.
In IgA nephropathy, miR-148b, which potentially targets core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 (C1GALT1), was upregulated [
22]. Nielsen et al. found 12 upregulated human miRNAs, including miR-152, in the serum of type 1 diabetes patients relative to age-matched healthy controls [
23]. Moreover, monocytes are critical in atherosclerotic lesion formation, and can be subdivided into classical and nonclassical subsets [
29]. Bidzhekov et al. studied miRNA expression profiles of atherosclerotic plaques and found that miR-99b and miR-152 were co-expressed in plaque tissue and classical monocytes [
24]. Taken together, these findings increase our understanding of the importance of miR-148/152 family in nontumor diseases.
Downregulation of miR-148/152 family
MiR-148/152 family members are decreased in various tumor types, indicating that they have the potential to act as tumor-suppressor miRNAs. Li et al. found miR-148b was underexpressed in liver cancer stem cells (LCSCs) [
30]. In a study of hepatic cell lines, Zhao et al. found that miR-148b was downregulated in the liver cancer cell lines HepG2, MHCC97L, and MHCC97H relative to the hepatic cell line L02 [
31]. Moreover, Huang et al. reported that miR-152 was downregulated in HBV-related HCC tissues compared with adjacent noncancerous hepatic tissues [
32]. In view of the above, we speculated that miR-148/152 family members were downregulated in hepatocellular carcinoma. Furthermore, in hepatoblastoma, the expression of miR-148a was demonstrated to be lower than that in hepatocellular carcinoma [
33].
In gastrointestinal cancers, Chen et al. noted that miR-148a and miR-152 were downregulated in cancer tissue and cancer cell lines [
7]. Furthermore, they also found that low expression of miR-148a and miR-152 correlated with increased tumor size and advanced pT stage [
7]. Moreover, the study of Zheng et al. revealed that the low expression of miR-148a was significantly associated with lymph node metastasis in gastric cancer [
5]. They further found that Rho-associated, coiled-coil containing protein kinase 1(ROCK1), which might be a target of miR-148a, was involved in miR-148a-induced suppression of gastric cancer cell migration and invasion [
5]. Especially, the studies of Song et al. showed that miR-148b was downregulated in gastric cancer [
34], colorectal cancer [
35] and suppressed cell growth by targeting cholecystokinin-2 receptor(CCK2R). These results highlighted that miR-148/152 family might play important roles in gastric cancer progression and would become a potential biomarker.
In a study of cholangiocarcinoma, DNA methyltransferase 1(DNMT1) was verified as a target for miR-148a and miR-152 and the expression level of these miRNAs was decreased in cancer cells [
36]. In pancreatic ductal adenocarcinoma, Liffers et al. reported that miR-148a exhibited significant downregulation compared with normal pancreatic ductal cells and further investigation proved that miR-148a regulated cell survival through targeting cell division cycle 25B(CDC25B) [
37]. Moreover, in an animal model of oral squamous cell carcinoma, Yu et al. observed that expression of miR-148b was downregulated among 12 miRNAs [
38].
Furthermore, the expression of miR-148/152 family members is low not only in digestive system, but also in genital system tumors. Zhou et al. observed that the expression of miR-152 was decreased in ovarian cancer tissue and ovarian cancer cell lines, but miR-148a expression was decreased only in cancer cell lines [
39]. Hiroki et al. noted that reduced miR-152 expression correlated significantly with poor overall survival and disease-free survival in endometrial serous adenocarcinomas [
40]. On the other hand, MiR-148a was also downregulated in hormone-refractory prostate cancer cells (PC3 and DU145) and overexpression of miR-148a could inhibite cell growth, cell migration, invasion by targeting Mitogen- and stress-activated kinase 1 (MSK1) [
41]. In cancer-associated fibroblasts, Aprelikova et al. showed that miR-148a was downregulated compared with matched normal tissue fibroblasts established from patients with endometrial cancer and wingless-type MMTV integration site family, member 10B (WNT10B) was a direct target of miR-148a [
42]. In some nontumor diseases, such as chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), miR-152 was significantly decreased in NK cells of CFS/ME patients compared with nonfatigued controls [
25].
In summary, studies of miR-148/152 family members showed that their expression levels decreased in HCC, LCSC, gastrointestinal cancers, cholangiocarcinoma, pancreatic ductal adenocarcinoma, oral squamous cell carcinoma, ovarian cancer, endometrial serous adenocarcinoma and prostate cancer. MiR-148/152 family members might be tumor-suppressive miRNAs in these tumors.