Spindle assembly checkpoint defects and chromosomal instability in head and neck squamous cell carcinoma

Abstract

Alterations in chromosomal number and structure are found in most solid malignancies including head and neck squamous cell carcinoma (HNSC), however, the presence of ongoing, chromosomal instability in HNSC and its relation to spindle assembly checkpoint defects has not been formally demonstrated. We investigated the status of chromosomal instability ( Key words: head and neck squamous cell carcinoma; chromosomal instability; spindle assembly checkpointHead and neck squamous cell carcinoma (HNSC) accounts for more than 40,000 new cancer diagnosis annually in the United States. 1 HNSC exhibits a significant degree of structural and numerical chromosomal alterations compared to other solid tumors of epithelial origin. 2 These chromosomal alterations include aneuploidy, translocations, as well as intrachromosomal amplification and deletion. These terms that describe chromosomal alterations merely refer to a state, whereas chromosomal instability refers to an increased rate of change in chromosomal structure. 3,4 A state of aneuploidy may not necessarily imply underlying chromosomal instability, as many hematologic malignancies demonstrate stably inheritable chromosomal alterations in the absence of ongoing CIN.Molecular genetic progression models and data on premalignant lesions have demonstrated that chromosomal loss occurs early in HNSC progression, accompanied by a high incidence of structural and numerical chromosomal aberrations. Recent investigation of genetic alterations in other malignancies has implicated chromosomal instability (CIN) as a major pathway for the genetic progression of malignancy, and was reported in lung, 5 prostate, 6 cervical, 7 endometrial, 8 breast, 9 multiple myeloma 10 and colorectal cancer. 11 HNSC and other solid tumors have a much lower frequency of microsatellite instability (MIN, sometimes referred to as sequence instability) when compared to MIN tumors such as hereditary non-polyposis colon cancer. 12 Aneuploidy present in premalignant oral lesions can predict risk of subsequent development of HNSC 13 and a similar phenomenon has been observed in laryngeal lesions as well. 14 Other studies have shown increased sensitivity to bleomycin-induced chromosomal breakage in lymphocytes from HNSC patients, 15,16 and cell line studies have implicated breakage-fusion-bridge cycles and altered spindle function as a feature of these chromosomal alterations. 17 Although mitotic abnormalities consistent with chromosomal instability due to defects in chromosomal segregation were described in this examination of cultured oral cancer cells, 17 formal analysis of the rate of formation of these alterations or chromosomal instability has not yet been described for HNSC.Multiple mechanisms of CIN have been proposed for solid tumors, including defects in chromosome cohesion and condensation, deregulated mitotic progression, as well as alterations in the spindle assembly checkpoint. 18 HNSC demonstrates alterations in multiple genes that control mitotic checkpoints, including p53, p16, p14 ARF and oth...

Downregulation of RAD17 in head and neck cancer

“…HRAD17 is located on chromosome 5q12-13.1, 27 and frequent deletion has been demonstrated in head and neck tumors and other tumor types, 8,24,25,29 implying the presence of tumor suppressor genes on this chromosome arm. We also found LOH in chromosome 5q in 70% of head and neck samples tested.…”

“…HNSCC is known to display a phenotype with profound chromosomal instability, 29 and the lack of hRAD17 expression would intuitively contribute to the development of this phenotype.…”

Correlation between reduced expression of the spindle checkpoint protein BubR1 and bad prognosis in tonsillar carcinomas

“…10 Under normal conditions, the spindle checkpoint ensures a correct distribution of the genomic material to the daughter cells during mitosis. Spindle checkpoint defects and CIN were demonstrated in squamous cell carcinomas of head and neck (SCCHN) in 2003, 11 and these cancers harbor defects in other genomic loci critical in tumor development and spindle checkpoint control, such as p53.…”

miR-125b promotes cell death by targeting spindle assembly checkpoint gene MAD1 and modulating mitotic progression

“…The fact that HNOC frequently exhibits alterations in mitotic checkpoint genes mirrors the criticality of SAC integrity in this disease. 18 As alteration of Mad1 levels by miR-125b can cause distinct cellular events such as apoptosis, it can be comprehended that suppressing high Mad1 levels might prove to be therapeutic in HNOC. However, it is crucial to reckon that miR-125b has other known and unknown targets across the cell cycle whereas Mad1 regulation could also be controlled by hitherto unknown miRNAs.…”

“…In the Indian subcontinent, it comprises of about 50% of all cancers. 17 CIN is a consistent property of primary head and neck tumours, 18 which makes it pertinent to describe SAC defects in HNOC. Meanwhile, 14 miRNAs are reported to be downregulated, while 29 are upregulated in HNOC.…”