Cellular localization of CIP2A determines its prognostic impact in superficial spreading and nodular melanoma

Abstract

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an important oncogene contributing to cancer progression partially by regulating cMYC and AKT. We examined CIP2A expression in cutaneous melanomas, its association with clinicopathological parameters and mapped molecular mechanisms regulated by CIP2A in vitro. CIP2A expression was analyzed by immunohistochemistry in 17 nevi, 132 primary melanomas and 49 metastases. Effects of siRNA-mediated down-regulation on proliferation, apoptosis and signaling pathways were assessed in melanoma cell lines. In superficial spreading melanomas (SSM), high nuclear CIP2A expression was associated with poor overall survival (OS) (P = 0.0018). Surprisingly, high cytoplasmic expression was related to improved relapse-free (P = 0.031) and OS (P = 0.014) in nodular melanomas (NM). In vitro experiments revealed that CIP2A can regulate proliferation and/or apoptosis partially through the PI3K/AKT pathway but also independently. In summary, CIP2A could represent a potential therapeutic target in SSM. However, in NM cytoplasmic CIP2A is associated with improved prognosis indicating that CIP2A has distinct, complex functions dependent on the molecular context and histological subtype. As seen in other cancer types, CIP2A can influence cMYC and AKT, but our data also suggest that in melanoma it has additional targets which need to be identified.

Leucine-rich repeat-containing protein 59 mediates nuclear import of cancerous inhibitor of PP2A in prostate cancer cells

“…Targeting this interaction would exclude CIP2A from the nucleus, ameliorating cell cycle deregulation by blocking CIP2A interactions with NEK2 and Plk1 [27,28]. Importantly, increased nuclear CIP2A was recently correlated with poor prognosis in superficial spreading melanomas (SSMs) while there was no correlation between cytoplasmic CIP2A and patient outcome [49] and further supports the CIP2A-LRRC59 interaction as a drug target. Mapping the amino acids important for the CIP2A-LRRC59 interaction could yield insight into inhibition of this protein-protein interaction (PPI).…”

Prognostic significance of CIP2A expression in solid tumors: A meta-analysis

“…Certain studies have proved CIP2A expression in tumor cells was correlated with poor prognosis [ 9 , 12 – 14 , 20 – 36 ]. However, some have shown no association with patient prognostic significance [ 37 , 38 ] and even improved prognosis in nodular melanomas [ 29 ]. The results of those individual studies were controversial.…”

Diagnostic spectrum of nodular melanoma

“…CIP2A is an important oncogene that contributes to the progression of the tumor by regulating cMIK and AKT (17). By means of immunohistochemical analysis it has been seen that the CIP2A levels increased in the tumor cells and its nuclear or cytoplasmatic localization (17). In nodular melanoma there is a high cytoplasmatic expression of CIP2A correlated with an increase in survival, whereas in SSM a high nuclear expression of the protein is correlated with poor survival.…”

“…In nodular melanoma there is a high cytoplasmatic expression of CIP2A correlated with an increase in survival, whereas in SSM a high nuclear expression of the protein is correlated with poor survival. This suggests that CIP2A has different functions depending on its molecular context and histologic subtype (17).…”

“…Recently the role of CIP2A (alkaline phosphatase inhibitor 2A) has also been studied. CIP2A is an important oncogene that contributes to the progression of the tumor by regulating cMIK and AKT (17). By means of immunohistochemical analysis it has been seen that the CIP2A levels increased in the tumor cells and its nuclear or cytoplasmatic localization (17).…”