WNT Signaling and HBP1-Associated Functional Analysis in Uterine Leiomyoma: Potential for a Pharmacological Approach to Disease Treatment
Jiang, Rulan.
2018
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Abstract: Uterine Leiomyomas (UL) are the most common tumors in women of
reproductive age, which leads to approximately 200,000 hysterectomies annually in the
United States. Although over 95% of UL tumors are benign, they destroy the function of the
uterus and cause abnormal uterine bleeding, anemia, pelvic pain, and recurrent pregnancy
loss. Activation of the WNT pathway is well established a... read mores a driver of cell proliferation
and tumorigenesis. In UL, cytogenetic deletion studies have shown that the chromosomal
region 7q22.3 is associated with UL in around 40% of patients. Furthermore, the tumor
suppressor HBP1, an inhibitor of Wnt signaling, is one of the 15 genes located by mapping
these deletions. Because HBP1, a repressor of Wnt signaling, lies in this minimally deleted
region, we hypothesized that decreased HBP1 expression may contribute to WNT signaling in
UL. Using patient samples obtained from hysterectomy, we showed the protein levels of
β-catenin, the signature signal in activation of Wnt signaling, increased in leiomyoma
compared to that in myometrium. Furthermore, Axin II mRNA, a common target gene of Wnt
signaling, also increased in fibroids. These results suggest activation of WNT signaling is
common in fibroid tumors. Furthermore, HBP1 also decreased in approximately 50% of
leiomyomas, consistent with the deletion studies. To identify whether decreased HBP1
defined a unique sub-type of fibroid tumor, we undertook an unbiased screen of UL patients
using RNAseq and bioinformatics analysis to identify global and HBP1-dependent changes in
UL. As predicted by previous published work, an ESR1-activated proliferation gene
expression signature was common in all leiomyoma samples. In tumors with normal HBP1
levels, cell cycle and GPCR signaling, cholesterol biosynthesis related gene signatures
were active compared to HBP1 low leiomyomas. In contrast, in the HBP1-low tumors, WNT
signaling, mRNA metabolism and translation signatures were present, consistent with qPCR
and Western Blotting results. In conclusion, these data demonstrate that the WNT signaling
pathway, and in particular the Wnt repressor HBP1, may play a critical role in pathogenesis
of leiomyoma.
Thesis (M.S.)--Tufts University, 2018.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisors: Amy Yee, and John Castellot.
Committee: Eric Paulson, and Emmaneul Pothos.
Keyword: Molecular biology.read less - ID:
- sf268h049
- Component ID:
- tufts:26054
- To Cite:
- DCA Citation Guide EndNote
