C-terminus of MUC16 activates Wnt signaling pathway through its interaction with β-catenin to promote tumorigenesis and metastasis

Qi, Lei; Cheng, Zhen; Luo, Lianzhong; Yang, Yun; Zhang, Zhenzhu; Ma, Huanhuan; Chen, Tao; Huang, Xi; Lin, Shu-Yong; Jin, Meijun; Li, Qinxi; Li, Xiaotong

doi:10.18632/oncotarget.9191

Cited by 34 publications

(41 citation statements)

References 59 publications

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“…The Wnt signaling pathway is involved in various malignant tumors, including ovarian cancer [ 6 , 12 – 14 ]. We therefore assessed the contribution made by Wnt signaling to CA125-induced ovarian cancer cell migration.…”

Section: Resultsmentioning

confidence: 99%

“…The extracellular region of MUC16, which is over-expressed in epithelial ovarian carcinoma, is cleaved from the cell surface and circulates in the blood. Known as CA125, this protein is a well-established ovarian cancer marker used for clinical diagnosis [ 6 ]. CA125 levels higher than 35 U/mL are considered abnormal and are associated with 90% of ovarian carcinomas, and are strongly associated with a poor prognosis [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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The effect of CA125 on metastasis of ovarian cancer: old marker new function

et al. 2017

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CA125 has been used extensively to screen for neoplasms, especially in ovarian cancer. The serum CA125 level can be used as a better prognosis evaluation and it may dynamic monitoring the disease progression. We explored the effect of CA125 on ovarian cancer cell migration and its underlying mechanism. Transwell assays showed that exposure to 0.2 μg/ml or 0.4 μg/ml CA125 for 48 h increased migration of A2780 and OVCAR-3 ovarian cancer cells. This effect of CA125 was blocked addition of 200 ng/ml DKK-1, a Wnt pathway inhibitor. Conversely, addition of CA125 reversed the inhibitory effect of Wnt inhibition in A2780 cells pretreated with DKK-1. Examination of CA125 levels in serum from 97 ovarian cancer patients revealed no relationship between a patient's age or CA125 level currently used clinically for ovarian cancer diagnosis and metastasis. However, using receiver operating characteristic (ROC) curves, we identified a new cut-off value for the serum CA125 concentration (82.9 U/ml) that is predictive of metastasis. The area under the curve is 0.632. This new cut-off value has the potential to serve as a clinically useful indicator of metastasis in ovarian cancer patients.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The effect of CA125 on metastasis of ovarian cancer: old marker new function

et al. 2017

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“…As a large glycoprotein, it is able to form a chemical barrier to protect the epithelium against hostile environmental conditions and pathogens [1,9]. However, cancer cells have an aberrant expression of mucins, which confers a number of oncogenic properties such as increased cell proliferation, evasion of the immune system and metastasis [1,3,10]. …”

Section: Importance Of Muc16 In Cancermentioning

confidence: 99%

“…CA125 is part of the extracellular portion of MUC16 that can be shed into the circulatory system [10]. Therefore, serum levels of CA125 are used to monitor disease status and recurrence after surgery or radiotherapy [13,14].…”

Section: Ovarian Cancermentioning

confidence: 99%

“…Furthermore, MUC16 has been reported to correlate with higher metastatic burden, and serum CA125 levels at baseline was a predictive factor for metastasis after resection [9,24,25]. A number of mechanistic studies have shown that MUC16 binds to mesothelin, E and P selectin and upregulates the FAK mediated Akt pathways, which confers metastatic properties [10,[26][27][28]. Other oncogenic properties of MUC16 include reprogramming metabolism [29] and increasing cell proliferation through JAK2 [30].…”

Section: Pancreatic Cancermentioning

confidence: 99%

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Targeting MUC16 in Cancer Therapy

Suh¹,

Valle²,

Morris³

2017

Chemotherapy (Los Angel)

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Over the recent decades, there has been a number of studies investigating the role of mucins in the pathogenesis of various cancers such as breast, lung, ovarian, gastrointestinal and pancreatic malignancies. Since then, it has been discovered that mucins play a critical role in tumorigenesis as they can mediate cell proliferation, metastasis and resistance to chemotherapy. Thus, mucins have been explored as a potential therapeutic target as well as a biomarker, as cancer cells often have an aberrant expression of mucins. MUC16 is a glycoprotein coded by one of the 21 mucin genes. CA125, the extracellular domain of MUC16, is a well-established biomarker for ovarian cancer, however there is no in depth literature review on MUC16 as a target for anti-cancer therapy. Thus, this review summarises the existing literature on MUC16, the current therapies targeting on MUC16 and highlights future avenues for targeting mucin-producing cancers.

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MUC16 C terminal fragment activates YAP1 through Src signaling to promote gallbladder cancer growth

Fan,

Wang,

Zhu

et al. 2023

MedComm – Oncology

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The Hippo pathway is crucial to organ size control and its dysregulation contributes to tumorigenesis. The aberrant activation of YAP1 was identified in gallbladder cancer (GBC). However, the underlying mechanism and role in GBC remains unclear. The C terminal fragment of Mucin16, also known as carbohydrate antigen 125 (CA125) encoded product, MUC16c, plays extensive roles in tumor initiation and development. Our study showed that MUC16c binding with 14‐3‐3ε disrupted the interaction of 14‐3‐3ε and phosphorylated yes‐associated protein 1 (YAP1), which led to the activation of YAP1 in GBC. Furthermore, MUC16c decreased the phosphorylation of YAP1 at serine 397 (ser397) by inhibiting LATS1, which upregulated YAP1 protein stability. Interestingly, there was a potential Src kinase site in the MUC16c fragment. The MUC16c_del15Y polypeptides with the deletion of the Src kinase site promoted the interaction of YAP1 with 14‐3‐3ε and downregulated the YAP1 protein levels. Consistently, SU6656, a Src kinase inhibitor also blocked the activation of YAP1 by MUC16c. The MUC16c_del15Y polypeptides decreased GBC cell proliferation in vitro and the growth of xenograft tumors in vivo. Our study revealed the underlying mechanism of the activation of MUC16c on YAP1 mediated by Src signaling and the antitumor effect of MUC16c_del15Y, providing a potential target for GBC therapy.

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C-terminus of MUC16 activates Wnt signaling pathway through its interaction with β-catenin to promote tumorigenesis and metastasis

Cited by 34 publications

References 59 publications

The effect of CA125 on metastasis of ovarian cancer: old marker new function

The effect of CA125 on metastasis of ovarian cancer: old marker new function

Targeting MUC16 in Cancer Therapy

MUC16 C terminal fragment activates YAP1 through Src signaling to promote gallbladder cancer growth

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