Department of Pathology, Yonsei University College of Medicine, 250 Seongsan-ro, Seodaemun-gu, Seoul, South Korea.
Mol Cancer Res. 2013 Jul;11(7):748-58. doi: 10.1158/1541-7786.MCR-12-0665. Epub 2013 Apr 17.
Ras association domain family 1 isoform A (RASSF1A) is a tumor suppressor that is methylated in many human cancers, including hepatocellular carcinoma (HCC). RASSF1A has been shown to suppress tumors via activation of the Hippo tumor suppressor pathway, including mammalian STE20-like kinase (MST). Amphiregulin (AREG), a target gene for Yes-associated protein (YAP), is a known oncogenic component of the Hippo pathway; however, the tumor-suppressive effect of RASSF1A on AREG in regard to regulation of the Hippo pathway remains unclear in HCC. Overexpression of RASSF1A in HCC cells, which lack functional RASSF1A, significantly inhibited cell proliferation and induced apoptosis by activating the Hippo pathway. Consequently, overexpression of RASSF1A inhibited the oncogenic functions of YAP, leading to a significant reduction in AREG secretion via regulation of the Hippo pathway. In human specimens, greater expression of RASSF1A was observed in chronic hepatitis/cirrhosis than in HCC, whereas expression of YAP and AREG was higher in 81% and 86% of HCC than in corresponding chronic hepatitis/cirrhosis, respectively. Furthermore, RASSF1A protein gradually decreased as multistep hepatocarcinogenesis progressed from chronic hepatitis/cirrhosis dysplastic nodules toward HCC, whereas the protein expression of YAP and AREG gradually increased. These findings provide mechanistic insight into the regulation of YAP and AREG by RASSF1A in human multistep hepatocarcinogenesis.
Ras 相关结构域家族 1 异构体 A（RASSF1A）是一种肿瘤抑制因子，在许多人类癌症中发生甲基化，包括肝细胞癌（HCC）。已经表明，RASSF1A 通过激活 Hippo 肿瘤抑制途径，包括哺乳动物 STE20 样激酶（MST），来抑制肿瘤。 Amphiregulin（AREG）是 Yes 相关蛋白（YAP）的靶基因，是 Hippo 途径中的已知致癌成分；然而，RASSF1A 对 Hippo 途径中 AREG 的肿瘤抑制作用在 HCC 中仍不清楚。在缺乏功能性 RASSF1A 的 HCC 细胞中过表达 RASSF1A，通过激活 Hippo 途径，显著抑制细胞增殖并诱导细胞凋亡。因此，RASSF1A 的过表达抑制了 YAP 的致癌功能，导致通过 Hippo 途径调节 AREG 的分泌显著减少。在人类标本中，慢性肝炎/肝硬化中 RASSF1A 的表达高于 HCC，而 YAP 和 AREG 的表达在 81%和 86%的 HCC 中分别高于相应的慢性肝炎/肝硬化。此外，随着多步骤肝细胞癌发生从慢性肝炎/肝硬化发育不良结节向 HCC 的进展，RASSF1A 蛋白逐渐减少，而 YAP 和 AREG 的蛋白表达逐渐增加。这些发现为 RASSF1A 在人类多步骤肝细胞癌发生中对 YAP 和 AREG 的调节提供了机制见解。
