Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA.
Ann Surg Oncol. 2018 Mar;25(3):792-800. doi: 10.1245/s10434-017-6296-2. Epub 2017 Dec 6.
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and few therapeutic options. Stathmin1 (STMN1) is a cytosolic protein involved in microtubule dynamics through inhibition of tubulin polymerization and promotion of microtubule depolymerization, which has been implicated in carcinogenesis and aggressive behavior in multiple epithelial malignancies. We aimed to evaluate expression of STMN1 in ACC and to elucidate how this may contribute to its malignant phenotype.
STMN1 was identified by RNA sequencing as a highly differentially expressed gene in human ACC samples compared with benign adrenal tumors. Expression was confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical (IHC) staining of a tissue microarray (TMA) from two independent cohorts. The biologic relevance of STMN1 was investigated in NCI-H295R cells by lentivirus-mediated silencing.
Differential gene expression demonstrated an eightfold increase in STMN1 messenger RNA (mRNA) in malignant compared with benign adrenal tissue. IHC showed significantly higher expression of STMN1 protein in ACC compared with normal and benign tissues. STMN1 knockdown in an ACC cell line resulted in decreased cell viability, cell-cycle arrest at G/G, and increased apoptosis in serum-starved conditions compared with scramble short hairpin RNA (shRNA) controls. STMN1 knockdown also decreased migration, invasion, and anchorage-independent growth compared with controls.
STMN1 is overexpressed in human ACC samples, and knockdown of this target in vitro resulted in a less aggressive phenotype of ACC, particularly under serum-starved conditions. Further study is needed to investigate the feasibility of interfering with STMN1 as a potential therapeutic target.
肾上腺皮质癌（ACC）是一种罕见的内分泌恶性肿瘤，预后差，治疗选择有限。Stathmin1（STMN1）是一种细胞溶质蛋白，通过抑制微管聚合和促进微管解聚来参与微管动力学，它与多种上皮恶性肿瘤的癌变和侵袭行为有关。我们旨在评估 STMN1 在 ACC 中的表达，并阐明其如何促成其恶性表型。
通过 RNA 测序，与良性肾上腺肿瘤相比，STMN1 被鉴定为人类 ACC 样本中高度差异表达的基因。通过定量逆转录聚合酶链反应（qRT-PCR）、Western blot 和两个独立队列的组织微阵列（TMA）的免疫组织化学（IHC）染色来确认表达。通过慢病毒介导的沉默在 NCI-H295R 细胞中研究了 STMN1 的生物学相关性。
差异基因表达显示恶性与良性肾上腺组织相比，STMN1 信使 RNA（mRNA）增加了八倍。IHC 显示 STMN1 蛋白在 ACC 中的表达明显高于正常和良性组织。与 scramble 短发夹 RNA（shRNA）对照相比，ACC 细胞系中 STMN1 的敲低导致细胞活力降低、细胞周期停滞在 G/G 期以及血清饥饿条件下的细胞凋亡增加。与对照相比，STMN1 的敲低还降低了迁移、侵袭和锚定非依赖性生长。
STMN1 在人类 ACC 样本中过度表达，体外敲低该靶标导致 ACC 的侵袭性表型降低，特别是在血清饥饿条件下。需要进一步研究以调查干扰 STMN1 作为潜在治疗靶点的可行性。
