WNT5a in Colorectal Cancer: Research Progress and Challenges

Figures & data

Figure 1 Canonical WNT signaling is transduced by the WNT/β-catenin and WNT/STOP (stabilization of proteins) signaling cascades through Frizzled (FZD) and LRP5/6 receptors, whereas non-canonical WNT signaling is transduced by the WNT/PCP (planar cell polarity), WNT/RTK (receptor tyrosine kinase), and WNT/Ca2+ signaling cascades through FZD and/or ROR1/ROR2/RYK receptors.

Figure 2 In WNT/PCP signaling pathway, WNT5a can activate Dvl by forming complexes with FZD and Ror2 receptors, and furthermore, small GTP enzymes of the Rho family are activated, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK), and in turn PCP pathway is activated. This process leads to the rearrangement of the cytoskeleton and regulating polarized cell morphology and migration within tissues.^33–36 WNT5a activation of the WNT/Ca2+ signaling pathway leads to the mobilization of free intracellular calcium, which regulates many cellular processes, including actin cytoskeleton remodeling and cell motility through activation of calcium-dependent signaling molecules.^37–41 In the canonical pathway, WNT5a plays two roles. On the one hand, WNT5a can activate canonical pathways to regulate embryogenesis and cell fate specificity. On the other hand, WNT5a can repress the canonical pathway by promoting glycogen synthase kinase3-independent degradation of β-catenin in regulating mammalian limb development.^42,43

Figure 3 WNT5a promotes the occurrence and development of colorectal cancer through multiple signal transduction pathways.

Table 1 WNT5a Promotes the Occurrence and Development of Colorectal Cancer Through Multiple Signal Transduction Pathways

Factors	Mechanism	Function	Reference
WNT5A+ TAM	WNT5A+TAMS expresses CCL2 through WNT5A-CaMKII-ERK pathway to promote the proliferation and metastasis of CRC.	CRC Promotion	[^Citation85]
Elaidic	Elaidic can up-regulate the expression of Wnt5A in APCnull HT29 cells, which can promote the EMT, of colorectal cancer cells, suggesting that it has the ability to promote tumor metastasis.	CRC Promotion	[^Citation68]
MiR-21b	There are many high binding sites between Wnt5A and Mir-21b. Studies have shown that Mir-21b promotes the metastasis of colorectal cancer cells by inhibiting Wnt5A.	CRC Promotion	[^Citation70]
CAMK2γ	WNT5a activates CAMK2 and promotes CAC by enhancing STAT3.	CRC Promotion	[^Citation74]
FZD2	FZD2 and Wnt5A interact and up-regulate through Fyn kinase-dependent STAT3 pathway, which promotes EMT and cell migration, and finally accelerates the process of colorectal cancer.	CRC Promotion	[^Citation80]
FOXM1	Up-regulation of FOXM1 by H3K79me2 can inhibit the mature phenotype and function of BMDCs through Wnt5a signal pathway.	CRC Promotion	[^Citation66]
TrpC5	The overexpression of TRPC5 increases the expression of Wnt5A, inhibits the differentiation of colorectal cancer cells, and increases the expression levels of CD44 and CD133, thus enhancing the dryness of colorectal cancer cells.	CRC Promotion	[^Citation87]

Table 2 WNT5a Inhibits the Occurrence and Development of Colorectal Cancer Through Multiple Signal Transduction Pathways

Factors	Mechanism	Function	Reference
ROR2	ROR2 is the receptor or coreceptor of Wnt5A and is regulated by Wnt5A. It can induce tumor cell cycle arrest and apoptosis by inhibiting catenin and AKT signal pathway, and then antagonize EMT and tumor stem cells.	CRC inhibition	[^Citation25,Citation90]
15-PGDH	WNT5A can promote the decomposition of prostaglandin E2 by up-regulating 15-PGDH, thus reducing inflammation and tumor growth in tumor microenvironment, and ultimately inhibiting colorectal cancer.	CRC inhibition	[^Citation96]
Fasn	Fasn knockout can weaken WNT signaling pathway by down-regulating WNT5a expression, at least partially inhibiting metastasis.	CRC inhibition	[^Citation98]
EZH2	The enrichment of EZH2 in the Wnt5A promoter region further up-regulated the expression of H3K27me3 and inhibited the expression of Wnt5A, thus inhibiting the transformation of epithelial endothelial cells induced by transforming growth factor-β and inhibiting tumor metastasis.	CRC inhibition	[^Citation101]
miR-335	MiR-335 can target Twist1 and suppress WNT5a, and in turn inhibit EMT process and the growth of CRC HCT116 cell line.	CRC inhibition	[^Citation102]
RSPO	RSPO2 can destroy the combination of Wnt5A and FZD7, inhibit the irregular Wnt signal pathway through the physical interaction between RSPO2 and FZD7, and then reduce EMT, thus preventing the metastasis of colorectal cancer.	CRC inhibition	[^Citation105]
Parafibromin	The overexpression of parafibromin has ability to repress ovarian cancer via down-regulating Wnt5a, VEGF, and MMP-9.	CRC inhibition	[^Citation106,Citation107]
PKCα	The overexpression of WNT5a can increase the level of PKCα, and in turn stimulate a phosphorylation on the serine residue 35 of RORa and then promote the β-catenin bond with the serine 35 of RORa, this combination represes the expression of target gene of the WNT/β-catenin-dependent signaling pathway and in turn reduces this pathway.	CRC inhibition	[^Citation110]
Twist and ZEB1	WNT5A inhibits EMT by down-regulating the key regulatory factors Twist and ZEB1 of EMT, thus weakening the motor and invasive ability of tumors.	CRC inhibition	[^Citation48]

Figure 4 WNT5a inhibits the occurrence and development of colorectal cancer through multiple signal transduction pathways.

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