Synergistic inhibition of hepatocarcinogenesis by green alga Ulva lactuca polysaccharide and 5-fluorouracil targeted SERPINH1.

[BACKGROUND] The serpin family H member 1 (SERPINH1) as a collagen-specific molecular chaperone, plays a crucial role in the biosynthesis of collagen. However, its function in hepatocellular carcinoma (HCC) is largely unexplored.

[PURPOSE] To elucidate the mechanism which the combination of Ulva lactuca polysaccharide (ULP) and 5-fluorouracil (5-FU) synergistically inhibits tumors via targeting SERPINH1.

[METHODS] This study employed in vitro (RAW264.7 and HepG2 cells) and in vivo (H22 tumor-bearing mouse and xenograft zebrafish) models to investigate the mechanisms behind the synergistic antitumor effects and attenuated cytotoxicity of the ULP and 5-FU combination. RNA sequencing (RNA-seq) coupled with bioinformatic analyses was employed to explore the potential carcinogenesis and tumor-suppressive roles of SERPINH1. Furthermore, siRNA-mediated knockdown of SERPINH1 was performed to confirm its functional significance in HCC.

[RESULTS] A combination of ULP and 5-FU augments tumor cell inhibition and alleviates oxidative stress damage caused by chemotherapy. ULP and 5-FU inhibited collagen secretion by downregulating SERPINH1 expression, thereby impairing extracellular matrix (ECM) deposition. Consequently, this led to the suppression of invasion and migration in HepG2 cells.

[CONCLUSION] ULP is identified as a novel natural agent that synergizes with 5-FU to suppress tumor progression, primarily by modulating the ECM. The combination treatment targets SERPINH1, inhibiting collagen-mediated ECM deposition and consequently reducing tumor cell migration and invasion.