Human epididymis protein 4 ( HE4), also known as WFDC2 , is a member of the whey acidic protein (WAP) family. HE4 is expressed at low levels in normal tissues but is highly expressed in ovarian cancer (OC) and endometrial cancer. It is a sensitive indicator for ovarian cancer detection and a tumor marker. It is another highly recognized ovarian cancer tumor marker after CA125.

(Data source: Saint John's Cancer Institute official website)

The role of HE4 in ovarian cancer cell proliferation and tumor growth

HE4 can promote cell proliferation by regulating cell cycle-related proteins and inducing cells to enter the S phase from the G0/G1 phase. In vivo experiments have also confirmed that HE4 knockout can inhibit the growth of ovarian cancer tumors. HE4 can activate the ERK/MAPK signaling pathway by directly binding to EGFR or indirectly activating the EGF/EGFR pathway, thereby promoting cell proliferation. HE4 binding to HDAC3 can activate the PI3K/AKT signaling pathway and promote cell proliferation. HE4 promotes the proliferation and invasion of ovarian cancer cells by activating the ERK/MAPK and PI3K/AKT signaling pathways. Overexpression of HE4 can activate ERK and AKT, thereby increasing cell proliferation, while silencing of HE4 inhibits these signaling pathways and reduces cell proliferation.

(Data source Anastasi E, et al. Int J Mol Sci. 2023)

Comparison of HE4 and CA125

CA125 was the first ovarian tumor marker used clinically. Before the advent of HE4, CA125 was the "gold standard" for the diagnosis of clinical ovarian cancer. CA125 combined with ultrasound testing is currently a common method for the clinical diagnosis of ovarian cancer. All patients with ovarian cancer will experience elevated HE4 levels. Compared with CA125, HE4 has higher sensitivity and specificity, especially in the early, asymptomatic stages of the disease. Therefore, HE4 is a good indicator for the early diagnosis of ovarian cancer. HE4 levels are not affected by the menstrual cycle or menopausal status. In premenopausal women, its specificity for ovarian cancer diagnosis is superior to that of CA125. The combination of HE4 and CA125 can reduce the missed diagnosis of biomarker-negative ovarian cancer and improve the sensitivity of ovarian cancer diagnosis and treatment monitoring.

(Data source: El Bairi K. Curr Drug Targets. 2020)

HE4 and non-ovarian cancer diseases:

HE4 and endometrial cancer: HE4 can be used as a prognostic biomarker for endometrial cancer, and serum HE4 levels can be used to monitor the recurrence of patients with endometrial cancer.

HE4 and dilated cardiomyopathy: In patients with dilated cardiomyopathy (DCM), HE4 expression is elevated in the kidney and secreted into the serum. Circulating HE4 induces fibroblast activation and is accompanied by phosphorylation of extracellular signal-regulated kinase (ERK). These are associated with cardiac remodeling and future adverse cardiovascular events.

(Data source: Yamamoto M, et al. J Am Heart Assoc. 2021)

HE4 and chronic obstructive pulmonary disease (COPD): HE4 expression and secretion are increased in the bronchial epithelium and peripheral plasma of COPD patients, and plasma HE4 is negatively correlated with lung function. Cigarette smoke promotes HE4 expression and secretion in bronchial epithelial cells, in part through oxidative stress. This in turn mediates IL-6 production through phosphorylation of NFκB-p65, contributing to airway inflammation. Increased HE4 release from bronchial epithelial cells promotes myofibroblast differentiation and fibroblast proliferation, exacerbating airway remodeling.

(Data source: Zhan Y, Chen J, Wu J, et al. Respir Res. 2022)