The application of the aberrant epigenetic modifications as diagnostic, prognostic and predictive biomarkers for CRC have been reported in numerous studies, which open new avenues for exploration of reliable and robust biomarkers to improve the management of CRC patients. Epigenetic biomarkers for CRC including methylated DNA, miRNAs, and blood-based methylation markers were found in clinical or experiment tests [
14]. Many types of circRNAs have been found in a variety of tumors, and may relate to cancer cell proliferation, metastasis, invasion or as potential biomarkers for detecting cancer [
4,
15]. It was reported that 11 circRNAs were upregulated and 28 circRNAs were downregulated in CRC tissues [
6], of which the most significantly downregulation circRNA was derived from PTK2 tumor suppressor gene [
16]. Recently, several circRNAs were found to be involved in the proliferation and metastasis of CRC, such as circular RNA circPPP1R12A [
17], circCCDC66 [
18], circRNA_104916 [
19], and circ_0055625 [
20]. These findings provided valuable insights into the development of novel potential therapeutic targets or biomarkers for CRC. Yang et al. reported that circ-FBXW7 as well as the encodes protein FBXW7–185aa have potential prognostic implications in brain cancer [
13]. FBXW7 as a potent tumor suppressor is one of the most common mutated genes in human cancers, which inhibits the progression of tumors by targeting specific substrates for ubiquitination and proteasomal degradation [
21,
22]. Loss or mutation of FBXW7 has been found in multiple human tumors including CRC, which suggest it can be as an independent prognostic marker in some tumors [
23,
24]. Our study first found that circ-FBXW7 was low expressed in CRC patients, and then we evaluated the effect of circ-FBXW7 on CRC by establishing the overexpressed and knockdown of circ-FBXW7 in SW480 and SW620 cancer cell lines. We used siRNA method to knockdown of circ-FBXW7 to loss of function and transfection plasmid to overexpress of circ-FBXW7 to gain of function. Our results showed that knockdown of circ-FBXW7 promoted SW480 and SW620 cells proliferation, migration, invasion, and the tumor growth. On the contrary, circ-FBXW7 overexpression inhibited CRC cells proliferation and migration as well as the growth of tumor weight.
As reported, circ-FBXW7 is abundantly expressed in the normal human brain, while it is reduced in clinical malignant glioma patients, and it is positively associated with glioblastoma patient OS [
13]. Consistently, low expression of circ-FBXW7 was found in CRC patients according to our study. Circ-FBXW7 exhibited the same phenomenon to CRC cells by in vitro and in vivo experiments. si circ-FBXW7 expression in SW480 and SW620 cells significantly improved the cell proliferation, colony formation, cell migration and invasion, whereas, the overexpression of circ-FBXW7 reversed the changes, which are consistent with FBXW7 functions in regulating the cancer cellular processes [
8,
11,
12,
23,
25]. In addition, some researchers found that the FBXW7 is a binding target protein like an intermediate adjustment involving several signaling pathways. mTOR is a major target for treatment human diseases including cancer. It is reported that loss of FBXW7 and deletion or mutation of PTEN can activate mTOR [
26]. Our study showed that the levels of mTOR were significantly enhanced in si circ-FBXW7 groups of SW480 and SW620 cells, while PTEN were significantly decreased. On the contrary, circ-FBXW7 overexpressed reduced mTOR expression and improved the expression of PTEN. Similar to FBXW7, PTEN is also a tumor suppressor and predictive marker for CRC patient outcome, which can induce the cell resistance [
27]. Furthermore, our findings showed that the level of NEK2 was remarkably elevated in si circ-FBXW7 CRC cell groups, but decreased in oe circ-FBXW7 CRC cell groups. NEK2 regulates tumor progression, drug resistance and tumorigenesis, which is considered to be a potential biomarker of cancers [
28]. The upregulation of NEK2 is linked to poor prognosis for CRC patients [
29], while NEK2 siRNA may be a useful method for treatment colorectal patients [
30]. These results indicate that circ-FBXW7 is a necessary factor in controlling the CRC cell process by regulating cancer cell generation and metastasis through inhibiting the NEK2, mTOR signal pathways and activating PTEN.