MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells

Abstract

MUC16/CA125 is a tumor marker currently used in clinics for the follow-up of patients with ovarian cancer. However, MUC16 expression is not entirely restricted to ovarian malignancies and has been reported in other cancers including breast cancer. Although it is well established as a biomarker, function of MUC16 in cancer remains to be elucidated. In the present study, we investigated the role of MUC16 in breast cancer and its underlying mechanisms. Interestingly, our results showed that MUC16 is overexpressed in breast cancer tissues whereas not expressed in non-neoplastic ducts. Further, stable knockdown of MUC16 in breast cancer cells (MDA MB 231 and HBL100) resulted in significant decrease in the rate of cell growth, tumorigenicity and increased apoptosis. In search of a mechanism for breast cancer cell proliferation we found that MUC16 interacts with the ezrin/radixin/moesin domain-containing protein of Janus kinase (JAK2) as demonstrated by the reciprocal immunoprecipitation method. These interactions mediate phosphorylation of STAT3 (Tyr705), which might be a potential mechanism for MUC16-induced proliferation of breast cancer cells by a subsequent co-transactivation of transcription factor c-Jun. Furthermore, silencing of MUC16 induced G2/M arrest in breast cancer cells through downregulation of Cyclin B1 and decreased phosphorylation of Aurora kinase A. This in turn led to enhanced apoptosis in the MUC16-knockdown breast cancer cells through Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptotic pathway with the help of c-Jun N-terminal kinase signaling. Collectively, our results suggest that MUC16 has a dual role in breast cancer cell proliferation by interacting with JAK2 and by inhibiting the apoptotic process through downregulation of TRAIL.

Clinical Value of Nipple Discharge and Serum Markers of Breast Cancer

“…Preoperative level of CEA and CA15-3 in serum were well known as a significant effect on prognosis of breast cancer [19,20]. Cancer antigen 125 (CA125) was found to be up-regulated in breast cancer tissues and not expressed in non-neoplastic ducts [21]. In this study, the nipple discharge and serum levels of the four biomarkers in malignant lesion were significantly higher than those in benign lesion patients (P<0.01).…”

The clinical utility of CA125/MUC16 in pancreatic cancer: A consensus of diagnostic, prognostic and predictive updates by the Chinese Study Group for Pancreatic Cancer (CSPAC)

“…Studies have analyzed the specific role of CA125/MUC16 in various types of cancer (2,(17)(18)(19)(20)(21). In breast cancer cells, MUC16 has been shown to interact with Janus kinase 2 (JAK2) and phosphorylates signal transducer and activator of transcription 3 (STAT3), eventually increasing the transcription of cyclin D1 for cell proliferation (18). CA125/MUC16 can affect the formation of the glycocalyx by interacting with galectin 1 and 3 in normal epithelial cells.…”

“…we recommend that the combination of CA125 and other serum/tissue biomarkers, or similar combined applications, such as CA19-9 levels along with 18 FDG pET/CT are important for the diagnosis, treatment and surveillance of patients with PC at follow-up.…”

“…In our previous study, we also found that CA125 expression was much higher in metastatic lesions and was related with the metastasis-associated burden. when 18 F-FDG PET/CT was not available, we used CA19-9 and CA125 levels to establish equations for metabolic tumor volume (MTV) and total lesion glycolysis (TLG) based on their functional properties reflecting metabolic tumor burden. Our results suggested that the metabolic tumor burden estimated by serum tumor biomarkers may be suitable for monitoring the response to treatment and the progression of pC (49).…”

“…Currently, pET has been widely used in clinical practice to improve diagnosis and regular reexamination by detecting metastasis, even when it is slight and asymptomatic (77,78). we recently proposed a promising method for the pre-operative prediction of the prognosis of patients with PC using the combination of 18 F-FDG pET/CT and serum CA19-9 levels (47). Due to the important role of CA125 for the diagnosis, prognosis and course monitoring of pC, the combination of serum CA125 and metabolic imaging with 18 F-FDG pET/ CT may be effective, but requires further validation.…”