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Abstract：
OBJECTIVE: To explore the effect and mechanism of relaxin (RLX) in the growth and metastasis of livercancer after combination treatment with transarterial chemoembolization (TACE).
METHODS: HCCLM3 and Huh-7 cells were adopted to evaluate the effect of tumor proliferation, migration, and invasion after RLX administration in vitro. The rabbit VX2 model was used to evaluate the biosafety, doxorubicin penetration, local tumor response, tumor metastasis, and survival benefit of RLX combined with TACE treatment.
RESULTS: RLX did not affect the proliferation, migration, or invasion of HCCLM3 and Huh-7 cells, and the expression of E-cadherin and HIF-1α also remained unchanged while the MMP-9 protein was upregulated in vitro. In the rabbit VX2 model, compared to the normal saline group (NS), RLX group (RLX) and TACE mono-therapy group (TACE), the group that received TACE combined with RLX (TACE + RLX) showed an improved local tumor response and survival benefit. Furthermore, TACE combined with RLX was found to reduce tumor metastasis. This combination therapy reduced the fibrotic extracellular matrix in the tumor microenvironment, allowing for better penetration of doxorubicin, improved infiltration of CD8+ T cells and affected the secretion of cytokines. Additionally, RLX combined with TACE was able to decrease the expression of HIF-1α and PD-L1. The biosafety of TACE combined with RLX was also confirmed.
CONCLUSIONS: RLX synergized with TACE by mitigating the fibrotic extracellular matrix and tumor hypoxic microenvironment, improving the therapeutic effect and inhibiting metastasis during the treatment of liver cancer.
METHODS: HCCLM3 and Huh-7 cells were adopted to evaluate the effect of tumor proliferation, migration, and invasion after RLX administration in vitro. The rabbit VX2 model was used to evaluate the biosafety, doxorubicin penetration, local tumor response, tumor metastasis, and survival benefit of RLX combined with TACE treatment.
RESULTS: RLX did not affect the proliferation, migration, or invasion of HCCLM3 and Huh-7 cells, and the expression of E-cadherin and HIF-1α also remained unchanged while the MMP-9 protein was upregulated in vitro. In the rabbit VX2 model, compared to the normal saline group (NS), RLX group (RLX) and TACE mono-therapy group (TACE), the group that received TACE combined with RLX (TACE + RLX) showed an improved local tumor response and survival benefit. Furthermore, TACE combined with RLX was found to reduce tumor metastasis. This combination therapy reduced the fibrotic extracellular matrix in the tumor microenvironment, allowing for better penetration of doxorubicin, improved infiltration of CD8+ T cells and affected the secretion of cytokines. Additionally, RLX combined with TACE was able to decrease the expression of HIF-1α and PD-L1. The biosafety of TACE combined with RLX was also confirmed.
CONCLUSIONS: RLX synergized with TACE by mitigating the fibrotic extracellular matrix and tumor hypoxic microenvironment, improving the therapeutic effect and inhibiting metastasis during the treatment of liver cancer.
摘要：
目的：探讨松弛素（RLX）在肝动脉化疗栓塞（TACE）联合治疗后肝癌生长和转移中的作用及其机制。
方法：采用HCCLM3和Huh-7细胞对肿瘤增殖的影响，迁移,和体外RLX给药后的侵袭。用兔VX2模型评价其生物安全性,阿霉素渗透，局部肿瘤反应，肿瘤转移，RLX联合TACE治疗的生存获益。
结果：RLX不影响增殖，迁移,或HCCLM3和Huh-7细胞的侵袭，E-cadherin和HIF-1α的表达也保持不变，而MMP-9蛋白在体外表达上调。在兔子VX2模型中，与生理盐水组（NS）相比，RLX组（RLX）和TACE单药治疗组（TACE），接受TACE联合RLX(TACE+RLX)治疗组的局部肿瘤反应和生存获益均得到改善.此外，发现TACE联合RLX可减少肿瘤转移。这种联合疗法减少了肿瘤微环境中纤维化的细胞外基质，允许阿霉素更好的渗透，改善CD8+T细胞的浸润并影响细胞因子的分泌。此外,RLX联合TACE能够降低HIF-1α和PD-L1的表达。TACE联合RLX的生物安全性也得到证实。
结论：RLX通过减轻纤维化细胞外基质和肿瘤缺氧微环境与TACE协同作用，在肝癌的治疗过程中提高治疗效果和抑制转移。
方法：采用HCCLM3和Huh-7细胞对肿瘤增殖的影响，迁移,和体外RLX给药后的侵袭。用兔VX2模型评价其生物安全性,阿霉素渗透，局部肿瘤反应，肿瘤转移，RLX联合TACE治疗的生存获益。
结果：RLX不影响增殖，迁移,或HCCLM3和Huh-7细胞的侵袭，E-cadherin和HIF-1α的表达也保持不变，而MMP-9蛋白在体外表达上调。在兔子VX2模型中，与生理盐水组（NS）相比，RLX组（RLX）和TACE单药治疗组（TACE），接受TACE联合RLX(TACE+RLX)治疗组的局部肿瘤反应和生存获益均得到改善.此外，发现TACE联合RLX可减少肿瘤转移。这种联合疗法减少了肿瘤微环境中纤维化的细胞外基质，允许阿霉素更好的渗透，改善CD8+T细胞的浸润并影响细胞因子的分泌。此外,RLX联合TACE能够降低HIF-1α和PD-L1的表达。TACE联合RLX的生物安全性也得到证实。
结论：RLX通过减轻纤维化细胞外基质和肿瘤缺氧微环境与TACE协同作用，在肝癌的治疗过程中提高治疗效果和抑制转移。
