Stress-induced phosphoprotein 1 mediates hepatocellular carcinoma metastasis after insufficient radiofrequency ablation

Abstract

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.

FKBP4 is a malignant indicator in luminal A subtype of breast cancer

“…CCT family members overexpression have been reported involved in gene expression and regulation of various carcinomas [28][29][30][31][32]. STIP1 and HSP90AB1 are found associated with cell metastasis, apoptosis and other oncogenic functions in human cancer cells [33]. In our study, higher expressions of six co-expressed genes were all significantly increased in LABC compared to adjacent healthy controls.…”

Amarogentin Inhibits Liver Cancer Cell Angiogenesis after Insufficient Radiofrequency Ablation via Affecting Stemness and the p53-Dependent VEGFA/Dll4/Notch1 Pathway

“…Although RFA is the most effective method for treating liver cancer other than liver transplantation and hepatectomy, an effective solution has not been found for the occurrence of residual cancer. The heat produced by RFA is not enough to kill marginal cancer cells; instead, it increases the malignant progression of liver cancer [ 3 ]. Sublethal heat treatment promotes liver cancer cell development of a spindle-like morphology and transformation CD133-positive liver cancer cells, which are progenitor-like cancer cells that are highly proliferative [ 4 ].…”

“…Residual cancer cells generally become more proliferative, motile, aggressive, and drug-resistant after iRFA [ 3 ]. These malignant changes in cells have been verified to confer stemness; that is, the fraction of liver cancer stem cells (LCSCs) substantially increased after iRFA [ 4 ].…”

Co-overexpression of STIP1 and Hsp90 correlates with progression and prognosis of lung adenocarcinoma

“…However, inhibiting the expression of STIP1 can block the interaction between STIP1-Hsp90 and showed an antitumor effect [21]. Research suggests that heat exposure can induce the formation of STIP1-HSP90 complex in liver cancer cells, which could shuttle epithelial transcription repressor Snail1 into nucleus and regulate mesenchymal gene transcription; however, blocking the binding of HSP90-STIP1 can reduce the invasion potential of HCC cells after heat exposure [30].…”