Evidences have shown that TRIM family proteins participate in the pathogenesis of various cancers [
3]. For example, TRIM24 [
24,
25] and TRIM29 [
26,
27] are up-regulated in CRC tissues and exert oncogenic functions on CRC. In the current study, TRIM14 expression was higher in CRC tissues than in paired normal colorectal tissues (Fig.
1). In line with our findings, previous studies have reported the overexpression of TRIM14 in HCC, OSCC, TSCC, osteosarcoma, glioma and breast cancer [
5‐
10]. On the contrary, decreased TRIM14 expression was observed in NSCLC [
4]. These results suggest the different expression pattern and function of TRIM14 in diverse cancers.
Distant metastases contributes to the high mortality rate in CRC patients [
1]. Tumor metastasis is a multistage process. Tumor cell migration and invasion are responsible for the infiltration of tumor cells into lymphatic vessels, blood vessels and distant organs, and represent for the key steps during tumor metastasis [
28,
29]. The function of TRIM14 in cancer cell migration and invasion has been described in osteosarcoma [
6] and OSCC [
7]. Consistently with the above reports, our data showed that TRIM14 knockdown inhibited CRC cell migration and invasion, while TRIM14 overexpression had opposite effects (Fig.
3). Our data further demonstrated the important role of TRIM14 in tumorigenesis.
Several cancer-related signaling pathways have been reported to be activated by TRIM14, such as AKT pathway in osteosarcoma [
6], NF-κB pathway in TSCC [
8], Wnt/β-catenin pathway in glioma [
10] and STAT3 in breast cancer [
9]. The present study focused on the STAT3 pathway, and the effects of TRIM14 on the other pathways will be considered in our future study. STAT3 signaling pathway plays an important role in tumor-related activities, such as cell proliferation, migration, invasion and metastasis [
11,
13]. Evidence has shown that STAT3 is constitutively activated in CRC [
30], which is critical for CRC cell growth, survival, invasion and migration [
14]. It has been demonstrated that SPHK1, which catalyzes the formation of sphingosine 1-phosphate (S1P) [
15], causes the persistent activation of STAT3 in colitis-associated CRC [
17]. In the present study, TRIM14 overexpression promoted CRC cell migration and invasion, which was counteracted by SKI-II or AG490, suggesting that SPHK1/STAT3 contributed to TRIM14-mediated CRC cell migration and invasion. Matrix metalloproteinases (MMPs) are key enzymes responsible for the degradation of extracellular matrix, thus involving in tumor metastasis [
31]. Numerous studies have suggested the increased expression and activity of MMP2 and MMP9 in CRC specimens [
32‐
35]. VEGF, an important signal protein, is associated with the progression, invasion and metastasis of CRC and may be independent prognostic marker for CRC patients [
36]. VEGF, MMP2 and MMP9 are known as transcriptional targets of the STAT3 signaling pathway [
22]. Here, TRIM14 overexpression increased the phosphorylation of STAT3, and the expression of its downstream targets MMP2, MMP9 and VEGF in CRC cells, further demonstrating the involvement of the SPHK1/STAT3 pathway in the function of TRIM14. TRIM14 contains the PRYSPRY domain, which is crucial for protein–protein interactions [
37]. A previous study has identified more than 70 TRIM14 interacting proteins, which are associated with protein ubiquitination [
4]. We speculated that TRIM14 may regulate SPHK1 expression via its interaction partner, although the precise mechanism how TRIM14 regulated the SPHK1/STAT3 pathway requires further investigation.