New Research Finds Important Roles of Heat Shock Factor 1 in Hepatoblastoma; Possible Use as a Biomarker and Therapeutic Target

Hepatoblastoma is a rare cancer in children, but the most commonly seen liver-specific malignancy in this patient population. The rarity of the disease, coupled with a largely incomplete understanding of this cancer type’s pathophysiology and molecular mechanisms of formation and advancement have played significant roles in the lack of new treatment options beyond traditional chemotherapeutic modalities and surgical resection, and in severe cases, the need for liver transplantation.

However, a new study from the University of Pittsburgh and the UPMC Newborn Medicine Program has uncovered important new findings related to the functions of the transcription factor know as heat shock factor 1 (HSF1) in hepatoblastoma.

The study, published in February 2023 in the American Journal of Pathology, was led by Edward H. Hurley, MD, assistant professor of Pediatrics in the Division of Newborn Medicine and UPMC Newborn Medicine Program. Dr. Hurley also is a researcher in the Monga Laboratory in the Department of Pathology where he focuses his research on hepatoblastoma.

Key Study Findings

Dr. Hurley and colleagues’ extensive experimentation in a novel small animal model of hepatoblastoma developed by the Monga Laboratory uncovered a broad swath of functions for the HSF1 protein in hepatoblastoma.

The authors conducted a meta-analysis of human hepatoblastoma gene expression sets, which uncovered an association between HSF1 activation and tumor differentiation and mortality. HSF1 was found at much higher levels in hepatoblastoma cells than in the cells of normal liver tissues.

“We found that as the level of HSF1 expressed in hepatoblastoma cells increased, so too did the lethality of the tumor,” says Dr. Hurley. “The more HSF1 present, the more aggressive and deadly the cancer. This is a highly important finding from our study."

HSF1 signaling in hepatoblastoma may involve both canonical and cancer-specific gene targets, and that YAP1 expression may lead to the dedifferentiation of hepatocytes to more hepatoblastoma-like cells, while β-Catenin acts as a cellular accelerant leading to increased growth of transformed cells.

“Our research also points us toward the use of HSF1 levels as a more sensitive biomarker of the disease, compared to using the AFP and Myc protein levels for this purpose,” says Dr. Hurley. “We’ll need to further investigate the correlation between HSF1 protein levels and post-translational modifications with patient data to validate the clinical utility of HSF1 as a biomarker.”

Dr. Hurley and colleagues study also is suggestive of pharmacologic targeting of HSF1. When inhibiting HSF1 levels, the team found that in early stages of hepatoblastoma, smaller and fewer tumors were seen.

“With inhibition, we also saw and enhancement in tumor cell death,” says Dr. Hurley. “Our studies clearly show that more aggressive forms of the disease rely upon upregulated HSF1 levels, so this gives us a potential path for combatting the more virulent forms of the disease that are currently difficult to treat and have generally poor outcomes comparatively speaking.”

Read the full text and details of Dr. Hurley and colleagues important new study using the link below.

Learn more about Dr. Hurley and his research.

Learn more about the research of the Monga Laboratory at the University of Pittsburgh

Reference

Hurley EH, Tao J, Liu S, Krutsenko Y, Singh S, Monga SP. Inhibition of Heat Shock Factor 1 Signaling Decreases Hepatoblastoma Growth Via Induction of Apoptosis. Am J Pathol. 2023 February; 193(2): P148-P160.