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Challenging role of Wnt5a and its signaling pathway in cancer metastasis (Review).

Zhu N, Qin L, Luo Z, Guo Q, Yang L, Liao D - Exp Ther Med (2014)

Bottom Line: Accumulating evidence indicates that Wnt5a exhibits paradoxical effects in various types of cancer metastasis.Therefore, the Wnt5a signaling cascade in cancer metastasis appears to be complex and may depend on binding receptors, downstream effectors, exogenous inhibitors and tumor microenvironments, as well as the extracellular matrix, particularly cell/tissue-tropic contexts.Furthermore, it is reasonable to hypothesize that Wnt5a and the involved signaling pathways may become molecular targets in the treatment of cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China ; Department of Urology, Second Affiliated Hospital of South China University, Hengyang, Hunan 421001, P.R. China.

ABSTRACT
Wnt5a is a noncanonical signaling member of the wingless-related/mouse mammary tumor virus integration family, which is involved in a wide range of cellular processes, particularly in cancer development and metastasis. Accumulating evidence indicates that Wnt5a exhibits paradoxical effects in various types of cancer metastasis. Therefore, the Wnt5a signaling cascade in cancer metastasis appears to be complex and may depend on binding receptors, downstream effectors, exogenous inhibitors and tumor microenvironments, as well as the extracellular matrix, particularly cell/tissue-tropic contexts. The aim of the present study was to summarize the previous findings on the roles of Wnt5a and the potential mechanisms in various types of cancer metastasis. Furthermore, it is reasonable to hypothesize that Wnt5a and the involved signaling pathways may become molecular targets in the treatment of cancer metastasis.

No MeSH data available.


Related in: MedlinePlus

Roles of Wnt5a in cancer metastasis- (A) promoting and (B) suppressive processes. Fzd, frizzled; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; AKT, protein kinase B; JNK, c-Jun N-terminal kinase; ARF-6, ADP-ribosylation factor 6; IL-10, interleukin-10; CAMKII, Ca2+/calmodulin-dependent protein kinase II; TLR4, Toll-like receptor 4; NFκB, nuclear factor κB; ROR2, receptor tyrosine kinase-like orphan receptor 2.
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f1-etm-08-01-0003: Roles of Wnt5a in cancer metastasis- (A) promoting and (B) suppressive processes. Fzd, frizzled; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; AKT, protein kinase B; JNK, c-Jun N-terminal kinase; ARF-6, ADP-ribosylation factor 6; IL-10, interleukin-10; CAMKII, Ca2+/calmodulin-dependent protein kinase II; TLR4, Toll-like receptor 4; NFκB, nuclear factor κB; ROR2, receptor tyrosine kinase-like orphan receptor 2.

Mentions: An early study of gene expression profiling found that Wnt5a/PKC signaling was associated with aggressive melanoma behavior (17). The Weeraratna group (26) used microarray analysis to demonstrate that Wnt5a directly promoted cell invasion and motility via the inhibition of metastasis-associated gene expression (KISS and CD44) and the stimulation of EMT (a key step in metastasis) in a PKC-dependent manner. Nomachi et al (27) found that ROR2, an orphan receptor belonging to the ROR family of receptor tyrosine kinases, played critical roles in Wnt5a-induced cell migration by regulating the formation of lamellipodia and the reorientation of the microtubule-organizing center (MTOC). ROR2 possesses an extracellular cysteine-rich domain that resembles the Wnt-binding sites of the Fzd proteins, thus, it is possible that ROR2 interacts with members of the Wnt family (28). RORs play critical roles in enhancing cell invasion and migration in multiple cancer types (29). Wnt5a stimulation induces the activation of c-Jun N-terminal kinase (JNK) at the wound edge in a ROR2-dependent manner, and inhibiting JNK activity abrogates Wnt5a-induced lamellipodia formation and MTOC reorientation. Additionally, the association of ROR2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. Thus, JNK may play roles in cell migration and invasion by phosphorylating the focal adhesion-associated protein, paxillin (30). Further study revealed that Wnt5a-induced JNK activation and MTOC reorientation can be suppressed by inhibiting PKC (31). Therefore, Wnt5a exhibits metastasis-promoting activities in several types of cancer through different signaling pathways (Fig. 1). These novel findings demonstrate the diversity of the noncanonical signaling pathways, as well as further the understanding of tumor metastasis.


Challenging role of Wnt5a and its signaling pathway in cancer metastasis (Review).

Zhu N, Qin L, Luo Z, Guo Q, Yang L, Liao D - Exp Ther Med (2014)

Roles of Wnt5a in cancer metastasis- (A) promoting and (B) suppressive processes. Fzd, frizzled; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; AKT, protein kinase B; JNK, c-Jun N-terminal kinase; ARF-6, ADP-ribosylation factor 6; IL-10, interleukin-10; CAMKII, Ca2+/calmodulin-dependent protein kinase II; TLR4, Toll-like receptor 4; NFκB, nuclear factor κB; ROR2, receptor tyrosine kinase-like orphan receptor 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061222&req=5

f1-etm-08-01-0003: Roles of Wnt5a in cancer metastasis- (A) promoting and (B) suppressive processes. Fzd, frizzled; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; AKT, protein kinase B; JNK, c-Jun N-terminal kinase; ARF-6, ADP-ribosylation factor 6; IL-10, interleukin-10; CAMKII, Ca2+/calmodulin-dependent protein kinase II; TLR4, Toll-like receptor 4; NFκB, nuclear factor κB; ROR2, receptor tyrosine kinase-like orphan receptor 2.
Mentions: An early study of gene expression profiling found that Wnt5a/PKC signaling was associated with aggressive melanoma behavior (17). The Weeraratna group (26) used microarray analysis to demonstrate that Wnt5a directly promoted cell invasion and motility via the inhibition of metastasis-associated gene expression (KISS and CD44) and the stimulation of EMT (a key step in metastasis) in a PKC-dependent manner. Nomachi et al (27) found that ROR2, an orphan receptor belonging to the ROR family of receptor tyrosine kinases, played critical roles in Wnt5a-induced cell migration by regulating the formation of lamellipodia and the reorientation of the microtubule-organizing center (MTOC). ROR2 possesses an extracellular cysteine-rich domain that resembles the Wnt-binding sites of the Fzd proteins, thus, it is possible that ROR2 interacts with members of the Wnt family (28). RORs play critical roles in enhancing cell invasion and migration in multiple cancer types (29). Wnt5a stimulation induces the activation of c-Jun N-terminal kinase (JNK) at the wound edge in a ROR2-dependent manner, and inhibiting JNK activity abrogates Wnt5a-induced lamellipodia formation and MTOC reorientation. Additionally, the association of ROR2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. Thus, JNK may play roles in cell migration and invasion by phosphorylating the focal adhesion-associated protein, paxillin (30). Further study revealed that Wnt5a-induced JNK activation and MTOC reorientation can be suppressed by inhibiting PKC (31). Therefore, Wnt5a exhibits metastasis-promoting activities in several types of cancer through different signaling pathways (Fig. 1). These novel findings demonstrate the diversity of the noncanonical signaling pathways, as well as further the understanding of tumor metastasis.

Bottom Line: Accumulating evidence indicates that Wnt5a exhibits paradoxical effects in various types of cancer metastasis.Therefore, the Wnt5a signaling cascade in cancer metastasis appears to be complex and may depend on binding receptors, downstream effectors, exogenous inhibitors and tumor microenvironments, as well as the extracellular matrix, particularly cell/tissue-tropic contexts.Furthermore, it is reasonable to hypothesize that Wnt5a and the involved signaling pathways may become molecular targets in the treatment of cancer metastasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China ; Department of Urology, Second Affiliated Hospital of South China University, Hengyang, Hunan 421001, P.R. China.

ABSTRACT
Wnt5a is a noncanonical signaling member of the wingless-related/mouse mammary tumor virus integration family, which is involved in a wide range of cellular processes, particularly in cancer development and metastasis. Accumulating evidence indicates that Wnt5a exhibits paradoxical effects in various types of cancer metastasis. Therefore, the Wnt5a signaling cascade in cancer metastasis appears to be complex and may depend on binding receptors, downstream effectors, exogenous inhibitors and tumor microenvironments, as well as the extracellular matrix, particularly cell/tissue-tropic contexts. The aim of the present study was to summarize the previous findings on the roles of Wnt5a and the potential mechanisms in various types of cancer metastasis. Furthermore, it is reasonable to hypothesize that Wnt5a and the involved signaling pathways may become molecular targets in the treatment of cancer metastasis.

No MeSH data available.


Related in: MedlinePlus