Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells

Abstract

Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/β-catenin signaling, but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 re-expression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma, and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression

Identification of key genes of papillary thyroid carcinoma by integrated bioinformatics analysis

“…Recently, a researcher has shown that abnormal expression of NMU is associated with a variety of cancers (33). For SERPINA1, there are currently 6 articles pointing out that SERPINA1 may be a key gene for PTC, consistent with our results (28,(34)(35)(36)(37)(38). Clinical studies have shown that high expression of TIMP1 is positively correlated with a poor prognosis of colon, brain, prostate, breast, lung, and several other cancers (39).…”

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

“…SERPINA1 is a serine protease inhibitor with targets including elastase, plasmin, thrombin, trypsin, chymotrypsin and plasminogen activator (79). SERPINA1 is regulated by prospero homeobox 1, which may enhance WNT/β-catenin signaling (79).…”

“…SERPINA1 is regulated by prospero homeobox 1, which may enhance WNT/β-catenin signaling (79). In general, SERPINA1 has been implicated to serve a role in the chemoresistance of ovarian cancers (79).…”

Signaling cascades in thyroid cancer: Increasing the armory of archers to hit bullseye

“…Prospero homeobox protein 1 (Prox1), a tumor suppressor is a frequently downregulated protein in thyroid cancer. Inhibition of Notch signaling in BCPAP cells triggered a simultaneous upregulation of PROX1 . Co‐inhibition of HEY1 and HEY2 resulted in significant upregulation of PROX1 in thyroid cancer (BCPAP and TPC1) cells.…”

“…Data indicated that NOTCH pathway was involved in downregulation of PROX1 in thyroid cancers and HEY1 and HEY2 combinatorially downregulated PROX1 (shown in Figure ). Tumor growth was markedly reduced in immunodeficient mice grafted with Prox1 expressing BCPAP‐ cells into the back skin . Therefore it was suggested that Notch signaling negatively regulated Prox1 and inhibition of Notch signaling may prove to be effective to increase the expression of tumor suppressor genes in thyroid cancer.…”