Endogenous HMGB1 Modulates Fatty Acid Metabolism of Hypoxic and Nutrient-poor Pancreatic Cancer Cells and Related Mechanism / 肿瘤防治研究

ABSTRACT

Objective To explore the role and mechanism of HMGB1 in the fatty acid metabolism reprogramming and mitochondrial fusion/fission of hypoxic and nutrient-poor pancreatic cancer cells. Methods The correlation between the expression level of HMGB1 in pancreatic cancer tissue and the survival rate of pancreatic cancer patients were analyzed by GEPIA database. CCK-8 assay was used to measure cell proliferation rate, and scratch test and Transwell chamber method were carried out to detect the effects of endogenous HMGB1 on the invasion and migration abilities of human pancreatic cancer cell line Patu8988 after hypoxic and nutrient-poor treatment. Laser confocal microscope was used to observe the changes of mitochondrial morphology of Patu8988 cells. Western blot was used to detect the expression levels of mitochondrial fusion/fission and de novo fatty acid synthesis-related proteins. Results GEPIA database analysis results showed that HMGB1 was highly expressed in pancreatic cancer tissues (P < 0.01), and the expression level was negatively correlated with the survival time of pancreatic cancer patients (P=0.00097). Knockdown of HMGB1 expression could inhibit the proliferation, invasion and migration abilities of Patu8988 cells under hypoxic and nutrient-poor conditions. However, mitochondrial fission in patu8988 cells was increased. Knockdown of HMGB1 in Patu8988 cells increased the expression of fission-related protein FIS1 while decreased the expression of p-DRP1(Ser637) and fusion-related protein MFN1 and MFN2 in hypoxic and nutrient-poor environment; ACLY, p-ACLY and FASN protein expression levels were down-regulated. Conclusion Endogenous HMGB1 can promote the fusion and inhibit the fission of mitochondria in hypoxic and nutrient-poor Patu8988 cells, maintain mitochondrial morphology and function, and thereby up-regulate ACLY protein expression and phosphorylation level, promote FA synthesis, and maintain the proliferation, invasion and migration abilities of pancreatic cancer cells.