Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Hepatology. 2014 Jun;59(6):2238-50. doi: 10.1002/hep.27030. Epub 2014 Apr 25.
It is unclear how proliferating cells elicit suppression on cell proliferation and how cancer cells evade this growth suppression. Using a loss-of-function screening of the human kinome and phosphatome to identify genes suppressing tumor initiation in human hepatocellular carcinoma (HCC), we identified 19 genes and characterized one of the top-scoring tumor suppressor candidates, protein tyrosine phosphatase receptor type F (PTPRF). We found that PTPRF was induced during cell proliferation by cell-cell contact. Ectopic expression of wild-type PTPRF, but not the phosphatase-inactive mutant, suppressed cell proliferation and colony formation in soft-agar assays. In contrast, PTPRF silencing led to cell hyperproliferation, enhanced tumor colony formation in soft agar, and increased xenograft tumor growth in nude mice. Mechanistically, PTPRF silencing showed aberrant ERK-dependent signaling including the phosphorylation/stabilization of v-myc avian myelocytomatosis viral oncogene homolog (MYC) through the direct activation of v-src avian sarcoma viral oncogene homolog (SRC) and suppression of PP2A. This PTPRF-mediated growth suppression during cell proliferation functioned independently of the Hippo-Yap pathway. Clinically, PTPRF was down-regulated in 42% HCC (37/89), 67% gastric cancer (27/40), and 100% colorectal cancer (40/40). PTPRF up-regulation was found in 24% HCC (21/89) and associated with better clinical outcomes.
A novel PTPRF-mediated growth suppression pathway was identified by way of a functional genomics screening in human hepatoma cells. Induction of PTPRF by cell-cell contact during cell proliferation quenched the activated ERK-dependent proliferation signaling to prevent cell hyperproliferation and tumor initiation. PTPRF down-regulation in HCC facilitated tumor development. Our findings shed light on how cancer cells can evade growth suppression and open a new avenue for future development of anticancer therapies.
目前尚不清楚增殖细胞如何引发细胞增殖抑制，以及癌细胞如何逃避这种生长抑制。本研究通过对人类激酶组和磷酸酶组进行功能丧失筛选，以鉴定抑制人肝细胞癌（HCC）肿瘤起始的基因，从而发现了 19 个基因，并对得分最高的候选肿瘤抑制因子之一蛋白酪氨酸磷酸酯酶受体 F（PTPRF）进行了特征描述。我们发现 PTPRF 在细胞接触诱导的细胞增殖过程中被诱导。野生型 PTPRF 的异位表达，但不是磷酸酶失活突变体，可抑制软琼脂测定中的细胞增殖和集落形成。相反，PTPRF 沉默导致细胞过度增殖，增强软琼脂中的肿瘤集落形成，并增加裸鼠中的异种移植物肿瘤生长。从机制上讲，PTPRF 沉默表现出异常的 ERK 依赖性信号，包括通过直接激活 v-src 禽肉瘤病毒癌基因同源物（SRC）和抑制 PP2A 来稳定和磷酸化 v-myc 禽髓细胞瘤病毒致癌基因同源物（MYC）。在细胞增殖过程中，这种由 PTPRF 介导的生长抑制作用独立于 Hippo-Yap 通路。临床上，PTPRF 在 42%的 HCC（37/89）、67%的胃癌（27/40）和 100%的结直肠癌（40/40）中下调，而在 24%的 HCC（21/89）中上调，与更好的临床结果相关。
通过人肝癌细胞的功能基因组筛选发现了一种新的 PTPRF 介导的生长抑制途径。细胞增殖过程中细胞接触诱导的 PTPRF 表达可抑制激活的 ERK 依赖性增殖信号，从而防止细胞过度增殖和肿瘤起始。HCC 中的 PTPRF 下调促进了肿瘤的发展。我们的研究结果揭示了癌细胞如何逃避生长抑制，并为未来开发抗癌疗法开辟了新途径。
