Transcriptional control of the MUC16 promoter facilitates follicle-stimulating hormone peptide-conjugated shRNA nanoparticle-mediated inhibition of ovarian carcinoma in vivo

Abstract

Ovarian cancer is the leading cause of cancer death among gynecological malignancies. The high mortality rate has not been significantly reduced despite advances in surgery and chemotherapy. Gene therapy shows therapeutic potential, but several key issues must be resolved before clinical application. To minimize toxicity in noncancerous tissues, tumor-specific ligands are conjugated to vectors to increase the selectivity of drug delivery. The expression pattern of follicle-stimulating hormone (FSH) receptor in normal and cancer tissues provides an opportunity for highly selective drug delivery in ovarian cancer. Furthermore, tumor-specific promoters can conditionally regulate therapeutic gene expression in tumor or normal tissues. The mucin 16 (MUC16) promoter might be a potential tool to drive ovarian cancer-localized gene expression since MUC16/CA125 is overexpressed in most ovarian carcinomas. Here, we screened the possible MUC16 promoter sequences and constructed MUC16 promoter-driven gro-α shRNA plasmid vectors. The vectors were specifically delivered into ovarian cancer cells via FSH peptide-conjugated nanoparticles. The predicted promoter sequence with TAAA repeats showed high transcriptional activity. The nanoparticle complex containing MUC16 promoter-driven gro-α shRNA and FSH peptides had the ability to decrease gro-α protein secretion in ovarian cancer cells and block tumor growth without obvious toxic effects in a nude mouse model bearing ovarian cancer. Our study provides a novel gene delivery system using a MUC16 promoter trigger and FSH peptide-mediated active targeting in ovarian cancer, and this system may be a promising strategy for specific genetic therapeutic delivery.

Recent Applications of Retro-Inverso Peptides

“…In particular, nanoparticles carrying the RI variant of the peptide FP21 showed to bind FSHR (Table 1). They were thus used as an ovarian cancer targeted delivery system [57][58][59], showing improved biostability compared to the parent peptide, with no degradation even after 12 h incubation with proteolytic enzymes. The data obtained on the RI peptide encouraged further developments and optimizations of the molecule for treating ovarian cancers expressing FSHR [57].…”

“…In another study, Zhang et al demonstrated that the RI derivative of the same peptide FP21 conjugated to nanocarriers had significantly enhanced anti-tumor effects working by reducing the tumor volumes in nude mice from 33.3% to 58.5%. This effect was likely amplified by the high resistance of the ligand to hydrolysis [57][58][59]. Another tumor promoter is the Transferrin receptor (TfR), an important transmembrane glycoprotein involved in iron transport.…”

Recent progress in research and application of engineered implanted cells for biomedical applications

“…5A). The typical design of artificial promoters is the combination of one or more tandem transcription factor binding sites whose activity are confined only in the cell state of interest and minimal promoter sequence [195][196][197][198][199][200]. Recently, the group of Wang Yangming from Peking University used miRNAs in the cell in combination with the CRISPRa/i system to construct a sensor element that can sense the state in the cell [194] (Fig.…”

Targeting CA-125 Transcription by Development of a Conditionally Replicative Adenovirus for Ovarian Cancer Treatment

“…An explanation for why CA-125 is highly expressed in gynecological cancer cells, especially in ovarian cancer cells, but rarely in other cancer cells remains elusive. Transcriptional regulation of MUC16 is also still poorly defined [ 16 , 17 ]. Thapi et al initially investigated the MUC16 promoter and planned to assess the putative transcriptional factor that controlled CA-125 expression, as presented in an AACR abstract in 2011 [ 16 ], but no follow-up information has been published.…”