Aim

Karyopherin α4 (KPNA4, importin α3) has been verified to be an oncogene in many cancers. However, its role in papillary thyroid cancer (PTC), the most frequent endocrine malignancy, is still unclear.

Materials and methods

KPNA4 expression was analyzed in PTC tissues and cells. The effects of KPNA4 on the proliferation, invasion, and apoptosis of PTC cells were evaluated after overexpression or downregulation of KPNA4. The influence of KPNA4 on NF-κB activation was evaluated by nuclear NF-κB p65 expression and NF-κB-luciferase reporter assays. Moreover, we also explored whether KPNA4 was regulated by miR-548b-3p. Additionally, the roles of miR-548b-3p and KPNA4 were explored in a xenograft mouse model.

Key findings

KPNA4 expression was increased in PTC tissues and cells, and its expression was significantly related to patients' clinicopathologic features and overall survival. Overexpression of KPNA4 significantly promoted PTC cell proliferation and invasion, enhanced nuclear p65 expression and augmented NF-κB luciferase activity. However, KPNA4 silencing showed opposite effects on the above indexes, and induced apoptosis of PTC cells. KPNA4 was a target of miR-548b-3p, which was downregulated in PTC and inhibited proliferation and invasion, but promoted apoptosis of PTC cells. KPNA4 overexpression abrogated the suppression of miR-548b-3p on the malignant phenotypes of PTC cells. Both miR-548b-3p overexpression and KPNA4 downregulation inhibited tumor growth and Ki-67 expression, elevated numbers of Tunel-positive cells, and deceased nuclear p65 expression in mouse tumor tissues.

Significance

KPNA4 was negatively regulated by miR-548b-3p and promoted the development of PTC via activating the NF-κB pathway.

中文翻译：

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miR-548b-3p调控的KPNA4促进甲状腺乳头状癌的恶性表型

目标

核仁蛋白α4（KPNA4，importinα3）已被证实是许多癌症中的癌基因。然而，其在乳头状甲状腺癌（PTC）（最常见的内分泌恶性肿瘤）中的作用仍不清楚。

材料和方法

在PTC组织和细胞中分析了KPNA4的表达。在KPNA4的过表达或下调后，评估了KPNA4对PTC细胞增殖，侵袭和凋亡的影响。通过核NF-κBp65表达和NF-κB-荧光素酶报告基因分析评估了KPNA4对NF-κB活化的影响。此外，我们还探讨了KPNA4是否受miR-548b-3p调控。此外，在异种移植小鼠模型中探索了miR-548b-3p和KPNA4的作用。

主要发现

KPNA4在PTC组织和细胞中的表达增加，并且其表达与患者的临床病理特征和总体生存率显着相关。KPNA4的过表达显着促进PTC细胞增殖和侵袭，增强核p65表达并增强NF-κB荧光素酶活性。但是，KPNA4沉默显示上述指标相反的作用，并诱导PTC细胞凋亡。KPNA4是miR-548b-3p的靶标，后者在PTC中被下调，抑制了增殖和侵袭，但促进了PTC细胞的凋亡。KPNA4过表达消除了miR-548b-3p对PTC细胞恶性表型的抑制作用。miR-548b-3p过表达和KPNA4下调均抑制肿瘤生长和Ki-67表达，Tunel阳性细胞数量增加，

意义

KPNA4被miR-548b-3p负调控，并通过激活NF-κB途径促进PTC的发展。