NPTX2 promotes colorectal cancer growth and liver metastasis by the activation of the canonical Wnt/β-catenin pathway via FZD6

Abstract

Accumulating evidence from clinical and epidemiological studies has highlighted the close correlation between the individual risk of cancer and nervous system diseases. The expression of neuronal pentraxin 2 (NPTX2) is absent in Alzheimer’s disease, anxiety, and depression. Herein, we found that NPTX2 mRNA and protein expression was significantly upregulated in colorectal carcinoma (CRC). NPTX2 expression level gradually increased with CRC progression and was closely associated with poor prognosis. In vitro and in vivo studies demonstrated that NPTX2 promoted CRC proliferation and metastasis through the activation of the Wnt/β-catenin signaling pathway. As NPTX2 receptors are absent on CRC cells, NPTX2 was shown to physically interact with frizzled class receptor 6 (FZD6) to promote β-catenin translocation into the cell nucleus, resulting in an increase in the expression of MYC, cyclin D1, snail, and N-cadherin along with a decrease in the expression of E-cadherin. Knockdown of FZD6 expression with a small-interfering RNA almost completely reversed the proliferative effects of NPTX2 on CRC development. In conclusion, NPTX2, a molecule related to nervous system diseases, promotes CRC cell proliferation and metastasis through the activation of the Wnt/β-catenin pathway via direct interaction with FZD6.

Combined Analysis of the Aberrant Epigenetic Alteration of Colorectal Cancer

“…Actually, previous studies indicated that HSPA1A [18,19], UNC5C [20,21], CBFA2T3 [22,23], NPTX2 [24,25], EPHX4 [26], and AQP1 [27][28][29] have been reported to be associated with CRC. This result also suggested the feasibility of our present results.…”

The Wnt Signalling Pathway: A Tailored Target in Cancer

“…Neuronal pentraxin 2 ( NPTX2 ) is a member of the neuronal pentraxin family and is essential for the formation of synapsis. NPTX2 was found overexpressed at both mRNA and protein level in CRC, particularly in metastatic lesions [ 29 ]. NPTX2 , which was found to positively correlate with tumour stages, lymphatic invasion, distant metastasis, and poor patients’ outcome, promotes β-catenin nuclear translocation and the expression of c-myc , cyclin D1, Snail , and N-cadherin .…”

“…No NPTX2 receptors have been identified in CRC; however, its cellular internalization was found mediated by the Wnt/β-catenin receptor, FZD6 . Additionally, it has been reported that NPTX2/FZD6 interaction translates in cancer cell proliferation and metastasis formation by triggering the Wnt/β-catenin pathway [ 29 ] ( Table 1 ).…”

Thrombospondin 2/Toll-Like Receptor 4 Axis Contributes to HIF-1α-Derived Glycolysis in Colorectal Cancer

“…The siRNAs for TLRs (TLR1-10) were purchased from GenePharma (Shanghai GenePharma Co., Ltd., Shanghai, China). Table S1 displays the sequences, and the experimental method was performed as previously described (15).…”