Helicase-like transcription factor exhibits increased expression and altered intracellular distribution during tumor progression in hypopharyngeal and laryngeal squamous cell carcinomas

Abstract

The helicase-like transcription factor (HLTF) belongs to the SWI/SNF family of proteins that use the energy from adenosine triphosphate hydrolysis to remodel chromatin during a variety of cellular processes. HLTF is also involved in DNA repair. Using computer-assisted microscopy, the immunohistochemical expression of HLTF was determined using a series of 100 hypopharyngeal and 56 laryngeal squamous cell carcinomas (SCCs) compared to tumor-free epithelia (60 cases) and dysplasias (92 cases). In hypopharyngeal SCC tumor progression, increased HLTF expression was associated with the percentage of immunopositive epithelial tissue areas (p=0.02) and the staining intensity of the positive area (p=0.0005). In the cases of laryngeal lesions, the immunolabeling intensity of HLTF significantly decreased with malignancy (p=0.01). We also observed a significant shift of HLTF expression from the cytoplasm toward the nuclear compartment (p=0.0007). Our data reveal an association between the presence of HLTF and neoplastic progression of hypopharyngeal and laryngeal SCCs.

The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor?

“…Although the nature of the immunodetected proteins was not investigated in that study, we suggest that truncated forms rather than wt HLTF were expressed in the positive tumor buds because estrogens favor HLTF mRNA splicing, which leads to the synthesis of the truncated proteins [6]. These shorter forms progressively replace wt HLTF during carcinogenesis in human cervical and hypopharyngeal cancers [10,14,15]. This switch from wt to truncated HTLF forms is also linked to a poor patient prognosis.…”

“…In addition, Hayward-Lester et al [6] described that the mRNA transcript of RUSH, the rabbit HLTF homolog, undergoes an estrogen-driven alternative splicing in the uterus, resulting in the retention of intron 21, which confers an early stop codon. A similar event was later described in HeLa cells (cervix adenocarcinoma) [10] without any evidence of hormone influence: the retention of intron 21 occurs alternatively with the retention or the loss of exon 20, which leads to frameshifts and early stop codons (Fig. 1).…”

“…The red crosses indicate the early stop codons, resulting from reading frameshifts. Adapted from [10] were decreased. In contrast, the HLTF protein levels were restored through proteasome inhibition, which suggested that USP7 protects HLTF from ubiquitin-proteasome-mediated degradation.…”

“…Studies on HLTF expression in head and neck or The number of patients (n) and the frequency (%) are indicated for each study. MSP methylation-specific PCR, MS-MLPA methylation-specific multiplexes ligation probe amplification cervix cancers (Table 4) demonstrated the alternative splicing of HLTF mRNA (see HLTF transcripts) leading to an increased expression of truncated protein forms [10]. These shorter protein forms lack domains involved in DNA repair (RING and helicases domains, see Fig.…”

“…1) and progressively replace wild-type HLTF during the head and neck or cervix oncogenic processes (Table 4). In head and neck cancers, Capouillez et al [10,14] focused on hypopharyngeal squamous cell carcinoma (HSCC) and laryngeal SCC (LSCC). In both cases, HLTF expression was assessed using immunohistochemistry (IHC) followed by microscopy computer-assisted quantification (percentage of immunopositive cells and staining intensity) and immunodetection on western blots (WB); subsequently, HLTF expression was correlated with the patient clinical outcome.…”