Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Oncogene. 2018 Jun;37(26):3514-3527. doi: 10.1038/s41388-018-0169-4. Epub 2018 Mar 21.
Recent studies indicated that insufficient radiofrequency ablation (RFA) could endow hepatocellular carcinoma (HCC) with higher aggressive potential. Stress-induced phosphoprotein 1 (STIP1), which was found highly expressed in HCC, is a chaperone molecule mediating cell homeostasis under thermal stress. We aimed to explore the role of STIP1 on the metastasis of residual HCC after RFA. Mice model with orthotopic HCC implants or caudal vein injection were employed to assess potential of lung metastasis and/or intrahepatic metastasis (IHM) of HCC cells. Cell culture model was used to determine cell invasion, mesenchymal marker genes expression, and underlying molecular mechanisms. Clinical specimens were collected to analyze the relationship between STIP1 and clinical outcome. We found that insufficient RFA elicited more IHM of HCCLM3 tumors, which could be reduced by silencing STIP1. Knockdown of STIP1 also significantly decreased lung metastatic potential of HCCLM3 cells. In vitro, HCCLM3 and HepG2 displayed a spindle-shaped morphology with upregulation of STIP1 and mesenchymal markers after sublethal heat exposure. Mechanistically, heat exposure induced the formation of STIP1-heat shock protein 90 (HSP90) complex, which could shuttle epithelial transcription repressor Snail1 into nucleus and regulate mesenchymal gene transcription. Blocking the HSP90-STIP1 complex reduced the invasive potential of HCC cells after heat exposure. Using clinical specimen, we found that STIP1 was expressed significantly higher in metastatic tumor tissues and in sera from metastatic HCC patients (p < 0.05). The high expression of STIP1 was significantly linked to shorter recurrence-free survival (p < 0.05). To sum up, our study found that STIP1 is positively associated with the sublethal heat-induced cancer cell metastasis through mediating the mesenchymal gene transcription. Blocking STIP1 activity may suppress HCC cell metastatic potential after RFA.
最近的研究表明，射频消融（RFA）不充分可能使肝细胞癌（HCC）具有更高的侵袭性。应激诱导磷蛋白 1（STIP1）在 HCC 中表达较高，是一种热应激下介导细胞内稳态的伴侣分子。我们旨在探讨 STIP1 在 RFA 后残余 HCC 转移中的作用。采用原位 HCC 移植或尾静脉注射小鼠模型评估 HCC 细胞肺转移和/或肝内转移（IHM）的潜能。细胞培养模型用于确定细胞侵袭、间充质标记基因表达及潜在的分子机制。收集临床标本分析 STIP1 与临床结局的关系。我们发现，不充分的 RFA 会引发更多 HCCLM3 肿瘤的 IHM，而沉默 STIP1 可减少这种情况。STIP1 敲低也显著降低了 HCCLM3 细胞的肺转移潜能。体外，HCCLM3 和 HepG2 在亚致死热暴露后呈现出纺锤形形态，STIP1 和间充质标记物上调。在机制上，热暴露诱导 STIP1-热休克蛋白 90（HSP90）复合物形成，可将上皮转录抑制因子 Snail1 易位到核内，并调节间充质基因转录。阻断 HSP90-STIP1 复合物可降低热暴露后 HCC 细胞的侵袭潜能。使用临床标本，我们发现转移性肿瘤组织和转移性 HCC 患者血清中 STIP1 的表达明显升高（p<0.05）。STIP1 的高表达与无复发生存时间缩短显著相关（p<0.05）。总之，我们的研究发现，STIP1 通过介导间充质基因转录与亚致死热诱导的癌细胞转移呈正相关。抑制 STIP1 活性可能会抑制 RFA 后 HCC 细胞的转移潜能。
