Differential expression and prognostic value of HMGA1 in pancreatic head and periampullary cancer

Abstract

The high mortality rate and minimal progress made in the treatment of pancreatic cancer over the last few decades, warrant an alternative approach. Treatment protocols should be individualised to the patient guided by prognostic markers. A particularly interesting target would be the architectural transcription factor high mobility group A1 (HMGA1), that is low or undetectable in normal tissue, induced during neoplastic transformation and consequently often exceptionally high in cancer. The aim of the current study was therefore to determine the differential expression of HMGA1 in pancreatic head and periampullary cancer and investigate its relation with outcome.

HMGA1 expression was determined by immunohistochemistry on original paraffin embedded tissue from 99 pancreatic head- and 112 periampullary cancers (with R0). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS) and conventional prognostic factors.

HMGA1 was expressed in 47% and 26% of pancreatic head- and periampullary cancer, respectively and associated with poor RFS, CSS and OS in periampullary cancer. CSS 5 years following surgery was 25% and 44% for patients with tumours which were positive or negative for HMGA1 protein, respectively. HMGA1 expression was not associated with survival in pancreatic head cancer.

In conclusion HMGA1 was identified as an independent prognostic marker predicting poor outcome in periampullary cancer. Although expressed to a higher extent as compared to periampullary cancer, HMGA1 was not associated with survival in pancreatic head cancer.

Introduction

With yearly mortality rates equalling incidence and a 5-year survival rate following diagnosis of 5%, pancreatic cancer remains a serious health problem.¹ Almost 80% of patients present with major vessel involvement or distant metastasis, precluding them from resection, currently still the only potential for cure. Even following the resection most patients will develop recurrent disease.² Despite attempts to improve outcome by several adjuvant chemo- and/or radio-therapy regimens, little to no progress has been made in the last few decades.³ Specialists therefore claim that therapy should be individualised to the patient, guided by prognostic markers. One such candidate marker could be high mobility group A 1 (HMGA1).

HMGA1 proteins, originally discovered in HeLa cells,⁴ are nuclear DNA-binding proteins which by interacting with the transcription machinery and altering chromatin structure, regulate the transcription of a multitude of genes.5, 6 HMGA1 has three isoforms encoded by the same gene, however generated through an alternative splicing mechanism.7, 8 HMGA1 is increased during embryogenesis and becomes low or undetectable in normal adult tissue.⁹ However, increased levels have also been observed in rat thyroid cell lines following transformation with oncogenes.10, 11 Furthermore, neoplastic transformation was associated with HMGA1 expression in human prostate-,12, 13 thyroid-,14, 15 colorectal-,16, 17, 18, 19, 20 cervix-,²¹ pancreas-,22, 23, 24 gastric-,²⁵ ovary-,²⁶ breast-,²⁷ liver-,²⁸ lung-,²⁹ uterine-³⁰ and head and neck-³¹ tissue and blood.³² A relation with worse pathological factors was observed in some of these.12, 13, 18, 20, 28, 33 Interestingly, following orthotopic injection of human pancreatic cancer cells, increased HMGA1 expression was observed in metastasis as compared to the primary tumour. A relation of HMGA1 expression with disease progression13, 20, 31 and poor survival24, 28, 29 was observed in some clinical studies. Of interest as well is the differential expression of HMGA1 between different neuroblastic tumours and different testicular germ cell tumours.34, 35

The expression of HMGA1 proteins in cancer cells and not in their normal counterparts makes it a particular interesting target for therapy. Adenovirus mediated suppression of HMGA1 inhibited cell growth in carcinoma cells derived from human thyroid, lung, colon and breast, however had no effect on normal thyroid cells in vitro. Furthermore, adenovirus-mediated suppression of HMGA1 in vivo reduced thyroid tumour size.³⁶ This growth inhibitory effect mediated by the suppression of HMGA1 was confirmed in pancreatic cancer.37, 38 Liau and co-workers showed that silencing of HMGA1-decreased anoikis resistance and cellular-invasiveness in vitro, metastatic potential in vivo and increased sensitivity to gemcitabine both in vitro and in vivo.38, 39, 40 They also provided evidence suggesting HMGA1 to be an independent predictor of poor postoperative survival in patients with pancreatic adenocarcinoma.²⁴

The evidence for an important role of HMGA1 proteins in tumour progression and the differential expression between subtypes of some tumours, prompted us to investigate the differential expression of HMGA1 in pancreatic head and the prognostically more favourable periampullary cancer and explore the relation with the outcome in both tumour types.