Expression of Par3 polarity protein correlates with poor prognosis in ovarian cancer

Nakamura, Hitomi; Nagasaka, Kazunori; Kawana, Kei; Taguchi, Ayumi; Uehara, Yuriko; Yoshida, Midori; Sato, Masakazu; Nishida, Hidetoshi; Fujimoto, Asaha; Inoue, Tatsuo; Adachi, Katsuyuki; Nagamatsu, Takeshi; Arimoto, Takahide; Oda, Katsutoshi; Osuga, Yutaka; Fujii, Tomoyuki

doi:10.1186/s12885-016-2929-2

Cited by 19 publications

(28 citation statements)

References 46 publications

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“…In addition, Par3 expression is more significantly upregulated in clinical metastatic PCa samples. Consistently, clinical studies by others in hepatocellular carcinomas [ 9 ], ovarian cancer [ 8 ] as well as clear cell renal cell carcinomas [ 34 ] demonstrated that Par3 acts as a positive regulator and is associated with a poor prognosis. More importantly, the present study showed that Par3 overexpression triggers expression of EMT-related genes such as Zeb1, Snail1, Twist1 and MMP1/9, by inactivation of metastasis-associated Hippo pathway [ 11 ].…”

Section: Discussionsupporting

confidence: 66%

“…Recent studies by several groups suggest that dislocalization of polarity proteins, Par3 and scribble, for instance, are intricately related to early stages of tumorigenesis via different signal transduction pathways [ 5 – 7 ]. In addition, it has been revealed that dys-regulation of Par3 is also associated with tumor metastasis and poor prognosis [ 5 , 8 , 9 ]. However, the exact role of Par3 in PCa metastasis is still poorly understood and the underlying molecular mechanisms are unclear.…”

Section: Introductionmentioning

confidence: 99%

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Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway

Zhou

Xue

Peng

et al. 2017

J Exp Clin Cancer Res

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BackgroundProstate cancer (PCa) is one of the most frequent tumors and leading cause of cancer deaths among males worldwide. The majority of deaths are due to recurrence and subsequent development of the metastatic cancer. Although loss or dislocalization of polarity proteins has been implicated in embryogenesis deficiency and tumorigenesis, association of polarity protein expression levels with tumor metastasis remains unclear.MethodsBioinformatics, qRT-PCR, western blot and immunohistochemical (IHC) analyses were used to examine expression of Par3, a key component of polarity-associated partitioning defective (PAR) complex, in primary and metastatic clinical PCa samples. Loss-of-function and gain-of-function studies in vitro and in vivo were performed to determine the functions of Par3 during metastasis of PCa. Co-immunoprecipitation (co-IP), western blot, immunofluorescence (IF), chromatin immunoprecipitation (ChIP) and qRT-PCR analyses were conducted to investigate the underlying mechanism for the function of Par3 on PCa metastasis.ResultsIn this study, we found that elevated expression of Par3 is positively associated with PCa metastasis. Knockdown of Par3 inhibits PCa cell migration and invasion in vitro and tumor metastasis in vivo, whereas overexpression of Par3 yields the opposite results. Mechanistically, Par3 suppresses phosphorylation of LATS to inactivate the Hippo pathway and enhances nuclear translocation of YAP by sequestrating KIBRA from the KIBRA/Merlin/FRMD6 complex and forming a Par3/aPKC/KIBRA complex. Stable knockdown of Par3 leads to restoration of the KIBRA/Merlin/FRMD6 complex and activation of the Hippo pathway, and then results in an inhibition on YAP nuclear translocation. In addition, in conjunction with the TEA domain (TEAD) transcription factor family, intranuclear YAP promotes the transcription of several pro-metastatic genes such as the matrix metalloproteinase (MMP) family, Zeb1, Snail1 and Twist1. Moreover, knockdown of Par3 downregulates expression of these pro-metastatic genes.ConclusionsOur findings indicate that elevated expression of Par3 promotes PCa metastasis via KIBRA sequestration-mediated inactivation of the Hippo pathway to upregulate expression of pro-metastatic genes. Downregulation of Par3 expression may serve as a potential treatment approach for PCa metastasis by activating the Hippo pathway.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0609-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway

Zhou

Xue

Peng

et al. 2017

J Exp Clin Cancer Res

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“…In human cancer, aPKCλ is often overexpressed, whereas for Par3 both increased and decreased expression was observed [ 10 – 14 ], suggesting that these proteins have opposite actions also in human malignancies. Different mouse tumor models confirmed that aPKCλ serves as a tumor promoter [ 15 ] whereas depending on the tumor settings Par3 indeed can serve both tumor-promoter and suppressor functions [ 4 , 13 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis

et al. 2018

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The polarity proteins Par3 and aPKC are key regulators of processes altered in cancer. Par3/aPKC are thought to dynamically interact with Par6 but increasing evidence suggests that aPKC and Par3 also exert complex-independent functions. Whereas aPKCλ serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKCλ genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKCλ, or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKCλ function as a complex to promote tumorigenesis. Molecularly, Par3/aPKCλ cooperate to promote Akt, ERK and NF-κB signaling during tumor initiation to sustain growth, whereas aPKCλ dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKCλ cooperate to drive Stat3 activation and hyperproliferation. Unexpectedly, the reduced inflammatory signaling did not alter carcinogen-induced immune cell numbers but reduced IL-4 Receptor-positive stromal macrophage numbers in all mutant mice, suggesting that epidermal aPKCλ and Par3 promote a tumor-permissive environment. Importantly, aPKCλ also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKCλ cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling.

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“…[3][4][5][6][7] However, in some other tumors, such as liver cancer, ovarian cancer, and renal clear cell carcinoma, PAR3 overexpression supports cancer cell proliferation and is associated with poor cancer prognosis. [8][9][10][11] All these evidences implicated the complex regulatory network of cell polarity and its interaction with oncogenic and tumor suppressor pathways. Recently, PAR3L has been identified as a new member of polarity protein family and exhibits pro-oncogenic activity by maintaining cell stemness and disrupting cell tight junctions.…”

Section: Discussionmentioning

confidence: 99%

“…However, all the growing evidences implicated the oncogenic role of PAR3. Increased PAR3 expression is evident in the metastatic human liver cancer and renal clear cell carcinoma [8][9][10] and correlated with the poor prognosis of ovarian cancer, 11 while knockdown of PAR3 delays the formation of papillomas by decreasing cell proliferation and increasing apoptosis. 12 Previously, a novel homolog of PAR3, PAR3-like protein (PAR3L), has been identified to colocalize with PAR3 at tight junctions.…”

Section: Introductionmentioning

confidence: 99%

High expression of partitioning defective 3–like protein is associated with malignancy in colorectal cancer

Liu

Jiang

et al. 2017

Tumour Biol.

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Partitioning defective 3-like protein is a novel cell polarity protein. Recently, partitioning defective 3-like protein has been demonstrated with tumor-promoting function by disrupting tight junction, inhibiting tumor suppressor liver kinase B1, and maintaining mammary stem cells. For the first time, we studied partitioning defective 3-like protein expression in malignant colorectal cancer. We used immunohistochemistry scoring system to evaluate partitioning defective 3-like protein expression in 196 colorectal cancer tissues and 33 adjacent normal tissues. We found that colorectal cancer tissues had much stronger partitioning defective 3-like protein immunoreactivity than normal tissues, and colorectal cancer patients with positive partitioning defective 3-like protein expression were characterized with higher cancer stages, metastasis, poor tumor differentiation, larger tumor size, as well as high levels of colorectal cancer markers carcinoembryonic antigen and cancer antigen 19-9. Besides, partitioning defective 3-like protein overexpression was independently predictive of lower survival rate in colorectal cancer patients, even after adjusting the influence of cofactors. Moreover, we also found that partitioning defective 3-like protein was associated with rapid growing colorectal cancer, while knockdown of partitioning defective 3-like protein expression largely inhibited cancer cell proliferation. Our study provided the first evidence that partitioning defective 3-like protein was overexpressed in colorectal cancer and associated with disease malignancy. Also, partitioning defective 3-like protein may serve as a promising prognostic marker and a potential therapeutic target for colorectal cancer treatment. Further study is necessary to understand the regulatory mechanism of partitioning defective 3-like protein in colorectal cancer and the feasibility of its application in clinic.

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Expression of Par3 polarity protein correlates with poor prognosis in ovarian cancer

Cited by 19 publications

References 46 publications

Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway

Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway

Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis

High expression of partitioning defective 3–like protein is associated with malignancy in colorectal cancer

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