Expression of 70-kDa heat shock protein in oral lesions: marker of biological stress or pathogenicity J. Kaur a , A. Srivastava b , R. Ralhan a, * a Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India b Department of Surgery, All India Institute of Medical Sciences, New Delhi, India Received 12 January 1998; received in revised form 23 February 1998; accepted 23 February 1998 Abstract We showed dierential expression of HSP70 during oral tumorigenesis. The precise functional role of HSP70 overexpression in the pathogenesis of betel and tobacco related oral cancer remains to be determined. To evaluate the utility of HSP70 as an indicator of the biological stress experienced by tumour cells or the malignant potential of oral epithelial lesions and predicting clinical out- come, its expression was assessed in dierent stages of oral carcinogenesis by immunohistochemical analysis and correlated with clinicopathological parameters. Overexpression of HSP70 protein was observed in 38 of 64 (59%) dysplastic lesions and 92 of 125 (74%) oral squamous cell carcinomas (SCCs) which included 76 of 105 cases (72%) of primary oral SCCs and 16 of 20 (80%) of recurrent oral SCCs. A signi®cant correlation of HSP70 expression was observed with severity of dysplasia (P=0.0006767), poor histological dierentiation of primary tumours (P=0.0184348), increase primary tumour size (P=0.0221103) and consumption of betel and tobacco (P<0.01). Follow-up studies showed that in patients with premalignant lesions the median transition time (pre- malignancy to malignancy) was signi®cantly shorter in HSP70 overexpressing cases than those showing basal level of HSP70 (P=0.012). Oral cancer patients with elevated levels of HSP70 showed decreased median disease-free survival time (no recurrence/ metastasis) than those showing basal HSP70 immunoreactivity (P=0.0246). The results suggest that HSP70 expression may not be a mere marker of biological stress but may also be implicated in the pathogenesis of oral cancer. # 1998 Elsevier Science Ltd. All rights reserved. Keywords: HSP70; Overexpression; Prognosis; Oral cancer; Dysplasia 1. Introduction Molecular chaperones are required for numerous fundamental biological processes especially in the recovery from cellular stress. Members of HSP70 family are involved in antigen processing and presentation through binding to short peptides thereby eliciting a strong anti-tumour immune response [1]. Both HSP60 and HSP70 participate in oncogene activation. The synthesis of HSPs can be induced by many viruses. However, the induction of HSP70 genes is not a general consequence of the stress caused by viral infection but represents a speci®c response, both with regard to the inducing virus and the target gene [2]. Human papil- loma viruses and human simian viruses are found to be associated with oral carcinogenesis. HSP70 expression is up-regulated by serum stimulation and by oncogenic viruses [3,4]. Overexpression of HSP70 confers tumor- igenicity to mouse ®brosarcama cells [5]. HSP70 synth- esis is closely related to the cell cycle. The cell cycle related regulation of HSP70 levels in HeLa cells (human uterine carcinoma cells) suggests a role for this protein in the control of mammalian cell growth [6]. Tumour cells, especially malignant tumour cells express elevated levels of HSP70 [7,8]. Overexpression of HSPs has been observed in cancers of lung, breast, pancreas, uterine cervix and urinary bladder [9±13]. We have previously reported dierential expression of HSP70 in oral tumorigenesis suggesting that in addition to tumour suppressor gene p53, the stress response pro- teins may also be implicated in oral oncogenesis [14,15]. To determine whether the elevated HSP70 levels in oral tumour cells are merely due to the stress experienced by these cells or has any functional signi®cance, HSP70 levels were studied in relation to the clinicopathological features of patients with premalignant and malignant oral lesions. The present study suggests implication of ORAL ONCOLOGY Oral Oncology 34 (1998) 496±501 1368-8375/98/$Ðsee front matter # 1998 Elsevier Science Ltd. All rights reserved. PII: S1368-8375(98)00064-5 * Corresponding author. Tel.: +91-11-6593478; fax: +91-11- 6862663; e-mail: rralhan@medinst.ernet.in