ΔNp63α‐dependent expression of Id‐3 distinctively suppresses the invasiveness of human squamous cell carcinoma

Higashikawa, Koichiro; Yoneda, Shingo; Tobiume, Kei; Saitoh, Masao; Taki, Masayuki; Mitani, Yoshitsugu; Shigeishi, Hideo; Ono, Shigehiro; Kamata, Nobuyuki

doi:10.1002/ijc.24280

Cited by 44 publications

(41 citation statements)

References 34 publications

(53 reference statements)

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“…We previously showed that ΔNp63α inhibits cancer cell migration, invasion, and metastasis by upregulating expression of the metastasis suppressor CD82, a member of the tetraspanin family of proteins (47), as well as MAP kinase phosphatase 3 (MKP3), which negatively regulates Erk2 signaling to inhibit cancer cell migration, invasion, and metastasis (45). In addition, ΔNp63α has been shown to regulate N-cadherin, L1 adhesion molecule, and Wnt-5A, which play a role in regulating cell migration (65), and to repress cell invasion by inhibiting Ets-1-mediated matrix metallopeptidase 2 (MMP2) expression via Id-3 up-regulation (66). Hence, ΔNp63α may act as a master regulator in regulation of cell motility.…”

Section: Discussionmentioning

confidence: 99%

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Liang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Activation of phosphatidylinositol 3 kinase (PI3K), Ras, and Her2 signaling plays a critical role in cancer development. Hotspot constitutive activating mutations in oncogenes, such as PIK3CA encoding the p110α catalytic subunit or RAS, as well as overexpression of Her2, are frequently found in human tumors and cancers. It has been well established that activation of these oncogenes profoundly promotes tumor metastasis, whereas decreased expression of ΔNp63α, the major protein isoform of the p53-related p63 expressed in epithelial cells, has been associated with cancer metastasis. In this study, we demonstrate that hotspot oncogenic mutations on PIK3CA and RAS, including p110α H1047R , K-Ras G12V , and H-Ras G12V , as well as activation of Her2, all led to suppression of ΔNp63α expression via Akt-fork-head transcription factor 3a (Akt-FOXO3a) signaling, resulting in increased cell motility and tumor metastasis. Expression of ΔNp63α effectively reversed p110α H1047R -, K-Ras G12V -, H-Ras G12V -, or Her2-induced cell motility in vitro and tumor metastasis in mouse models. We show that ΔNp63α was a direct FOXO3a transcriptional target and that expression of FOXO3a and ΔNp63α was correlated in human cancer biopsy samples. Together, these results demonstrate that ΔNp63α is a common inhibitory target of oncogenic PI3K, Ras, and Her2, and that ΔNp63α may function as a critical integrator of oncogenic signaling in cancer metastasis.PIK3CA | Ras | Her2 | ΔNp63α | cancer metastasis

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Section: Discussionmentioning

confidence: 99%

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Liang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Several recent findings [119][120][121] allow me, here, to propose the hypothesis that p63 is an epithelial organizer, and is involved as a modulator of EMT. This hypothesis would reconcile several apparently discordant functions of DNp63 during the development of epithelia, as well as in cancer biology, namely the activation of apparently distinct pathways discussed above: stemness, cytokeratins, adhesion molecules, differentiation proteins and cell cycle regulators.…”

Section: Np63mentioning

confidence: 98%

“…105 The expression of DNp63 is downregulated during EMT by the signaling molecule SNAIL, and this enhances the invasiveness of squamous cell carcinoma (SCC) cells in parallel with, and independently of, the downregulation of E-cadherin. 119,120 Depletion of DNp63a and DNp63b induces EMT in breast cell lines; 122 conversely, DNp63g per se is able to cause EMT with elevated TGFb-1, -2, -3 and its downstream effectors Smads2/3/4 via a p63-binding site in intron 1 of TGFb. 122 These data are compatible with p63 expression in presarcoma lesions versus sarcoma.…”

Section: Np63mentioning

confidence: 99%

p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53

2011

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p53 mutations, occurring in two-thirds of all human cancers, confer a gain of function phenotype, including the ability to form metastasis, the determining feature in the prognosis of most human cancer. This effect seems mediated at least partially by its ability to physically interact with p63, thus affecting a cell invasion pathway, and accordingly, p63 is deregulated in human cancers. In addition, p63, as an 'epithelial organizer', directly impinges on epidermal mesenchimal transition, stemness, senescence, cell death and cell cycle arrest, all determinant in cancer, and thus p63 affects chemosensitivity and chemoresistance. This demonstrates an important role for p63 in cancer development and its progression, and the aim of this review is to set this new evidence that links p63 to metastasis within the context of the long conserved other functions of p63.

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“…47 Also, DNp63 downregulation has been described as stimulating the invasive behavior of human squamous cell carcinoma and knockout of DNp63 in breast cancer cell lines induces epithelial-to-mesenchymal transformation (EMT). 47,48 Interestingly, Wnt/b-catenin signaling, which was activated in the tubal intraepithelial lesions from our experimental animals, has also been described to play an important role in the induction of EMT and metastasis in cancer. 49,50 As ovarian cancer in women is highly invasive, rapidly spreading disease in the abdomen, special attention was paid to tissues in close proximity to the bursa surrounding the ovary.…”

Section: Discussionmentioning

confidence: 61%

A mouse model for endometrioid ovarian cancer arising from the distal oviduct

Horst

Zee

Heijmans-Antonissen

et al. 2014

Intl Journal of Cancer

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Ovarian cancer is the deadliest gynecological malignancy in Western countries. Early detection, however, is hampered by the fact that the origin of ovarian cancer remains unclear. Knowing that in a high percentage of endometrioid ovarian cancers Wnt/b-catenin signaling is activated, and in view of the hypothesis that ovarian cancer may originate from the distal oviduct, we studied mice in which Wnt/b-catenin signaling was activated in M€ ullerian duct-derived tissues. Conditional adenomatous polyposis coli (Apc) knockout mice were used to study the activation of Wnt/b-catenin signaling in M€ ullerian duct-derived organs. These Pgr Cre/1 ;Apc ex15lox/lox mice (n 5 44) were sacrificed at 10, 20, 40 and 80 weeks and uterus, oviduct, ovaries and surrounding fat tissues were assessed using immunohistochemistry. Using nuclear b-catenin staining, Wnt/b-catenin signaling activation was confirmed in the entire epithelium of the adult M€ ullerian duct (fimbriae, oviduct and endometrium), but was absent in ovarian surface epithelium cells (OSEs). Besides endometrial hyperplasia, in 87.2% of mice intraepithelial lesions of the distal oviduct were found, whereas OSEs remained unaffected. In addition, 62.5% of mice developed tumors in the distal and fimbrial part of the oviduct. In the ovaries, mainly at young age, in 16.3% of mice, simple epithelial cysts were noted, which developed further into endometrioid ovarian tumors, resembling human endometrioid ovarian cancer (27.9% of mice). Next to this, locoregional growth in the utero-ovarian ligament was also shown. Here, for the first time, mutations (activation of Wnt/b-catenin) in the distal oviduct result in precursor lesions that develop into ovarian tumors, resembling human endometrioid ovarian cancer.Epithelial ovarian cancer is the deadliest gynecological malignancy in Western countries, accounting for more than 140,000 deaths each year worldwide. 1 As ovarian cancer survival is highly dependent on the tumor stage at diagnosis, early detection is key to decreasing death rate. Unfortunately, the origin of ovarian cancer remains unclear, making early discovery very difficult.For decades, ovarian surface epithelial cells (OSEs) have been appointed as the primary origin of epithelial ovarian cancer despite the fact that precursor lesions were never found.2 Over recent years, however, researchers have proposed different origins for epithelial ovarian cancer: the secondary M€ ullerian system, 3 the distal oviduct and fimbriae 4,5 and recently the transitional zone between OSEs and mesothelium at the hilial region of the ovary.6 Dubeau 3 and Piek et al. 7 were among the first to question OSEs as the only origin of ovarian cancer. In his original article, Dubeau 3 argues that the strong resemblance of ovarian epithelial tumors to tumors arising from organs embryologically derived from the M€ ullerian ducts and warrants the consideration that components of the secondary M€ ullerian system play a role in ovarian tumorigenesis. Piek et al. described dysplastic lesions in prophylac...

show abstract

ΔNp63α‐dependent expression of Id‐3 distinctively suppresses the invasiveness of human squamous cell carcinoma

Cited by 44 publications

References 34 publications

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53

A mouse model for endometrioid ovarian cancer arising from the distal oviduct

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