AHNAK suppresses tumour proliferation and invasion by targeting multiple pathways in triple-negative breast cancer

Abstract

BackgroundAHNAK, also known as desmoyokin, is a giant protein with the molecular size of approximately 700 kDa and exerts diverse functions in different types of cancer.ResultsIn the present study, we demonstrated that AHNAK mRNA levels were down-regulated in 7 out of 8 human breast cancer cell lines, especially in triple - negative breast cancer (TNBC) cell lines. Moreover, in patients with TNBC, the expression of AHNAK gene was inversely correlated with the tumor status (P = 0.015), lymph node status (P < 0.001), lymph node (LN) infiltration (P < 0.001) and TNM stage (P < 0.001). Moreover, down-regulated AHNAK expression was considered an independent prognostic factor associated with the poor survival of patients with TNBC. Overexpression of AHNAK in two TNBC cell lines, MDA-MB-231 and BT549, suppressed the in vitro TNBC cell proliferation and colony formation, and inhibited the in vivo TNBC xenograft growth and lung metastasis. The tumor suppressing effect of AHNAK in TNBC was associated with the AKT/MAPK signaling pathway and Wnt/β-catenin pathway. Consistent results were observed when AHNAK was knockdown in BT20 and MDA-MB-435 cells.ConclusionsTaken together, our results suggest that AHNAK acts as a tumor suppressor that negatively regulates TNBC cell proliferation, TNBC xenograft growth and metastasis via different signaling pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0522-4) contains supplementary material, which is available to authorized users.

Quantitative Proteomic Analysis Identifies AHNAK (Neuroblast Differentiation-associated Protein AHNAK) as a Novel Candidate Biomarker for Bladder Urothelial Carcinoma Diagnosis by Liquid-based Cytology

“…AHNAK was described as a nucleoprotein in neuroblastoma cell lines, where its expression was significantly suppressed (36), whereas in a study of melanoma, immunoreaction was observed mainly in the cytoplasm of normal cells, as oppose to loss of expression in melanoma cells (35). Based on these observations, the authors suggested that AHNAK may have a tumor suppressor role, which is in accord with our findings, as well as those of other studies (39,43). In our study, the levels of AHNAK protein and transcript were both significantly decreased in bladder urothelial carcinoma compared to benign urothelial lesion samples, based on proteomics and TCGA data.…”

“…When AHNAK was initially identified in normal bovine muzzle epidermal cells, immunofluorescent microscopy revealed a patchy staining pattern along the cytoplasmic membrane (40); however, various other cell-type-specific intracellular locations have been described in further reports (38,41). Absence of uniform expression of AHNAK has consistently been described in malignant tumors, with diverse intracellular localization depending on the type of tumor cell (38,(41)(42)(43)(44). AHNAK was described as a nucleoprotein in neuroblastoma cell lines, where its expression was significantly suppressed (36), whereas in a study of melanoma, immunoreaction was observed mainly in the cytoplasm of normal cells, as oppose to loss of expression in melanoma cells (35).…”

Análise De Expressão Gênica Na Identificação De Potenciais Marcadores Preditivos Em Neoplasias Malignas Mamárias

“…Contudo, a maioria dos trabalhos de expressão gênica avalia somente o potencial prognóstico dos genes, enquanto uma quantidade reduzida analisa o poder preditivo de genes em amostras de neoplasias primárias e metástases de linfonodos em câncer de mama (BERTUCI et al, 2000;HUANG et al, 2003;ABBA et al, 2007;FENG et al, 2007;WANG et al, 2013;VALENTE et al, 2014;CHEN et al, 2017;PAULA et al, 2017). Além disso, o significado biológico do envolvimento dos linfonodos e sua utilidade na orientação da terapia adjuvante e sistêmica tem sido objeto de muitos resultados discordantes (BERTUCI et al, 2000;HUANG et al, 2003;ABBA et al, 2007).…”

“…Em relação à análise de expressão em genes individuais como potenciais fatores preditivos em tumores mamários, também há poucos estudos publicados na literatura (WANG et al, 2013;SHRIVER;HUEMAN;ELLSWORTH, 2014;PAULA et al, 2017;CHEN et al, 2017). Shriver, Hueman e Ellsworth (2014) detectaram a expressão diferencial dos genes DKK1, IGJ, SCGB1D2, SERPINA1, TFF1, TFF3 e TMSB15A quando compararam neoplasias malignas primárias obtidas de pacientes linfonodo negativo com neoplasias malignas primárias linfonodo positivo, sugerindo esses genes como potenciais marcadores preditivos em câncer de mama.…”

“…Os autores encontraram expressão aumentada para esse gene no tumor primário quando comparado ao tecido adjacente; e relacionaram esse resultado com a proliferação tumoral e envolvimento dos linfonodos. Chen et al (2017) avaliaram a expressão do gene AHNAK, envolvido na via de sinalização Wnt, em amostras de carcinoma mamário triplo-negativo no sentido de elucidar o poder prognóstico e preditivo desses genes em câncer de mama. A expressão reduzida observada para o gene AHNAK foi correlacionada negativamente às características clinicopatológicas, tais como tamanho do tumor e envolvimento de linfonodos, concluindo que a expressão reduzida de AHNAK pode ter contribuído para a metástase linfonodal.…”