1. Molecular Stress and Stem Cell Biology Group, School of Biotechnology, KIIT University, Bhubaneswar, Odisha-751024, India
2. Department of Surgical Oncology, Kalinga Institute of Medical sciences, Bhubaneswar, Odisha-751024, India.
3. Department of Pathology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, odisha-751024, India
4. Department of Pathology, Apollo Hospitals, Bhubaneswar, Odisha-751004, India.
5. Department of Surgical Oncology, Apollo Hospitals, Bhubaneswar, Odisha-751004, India
6. Genome Stability Laboratory, Yong Loo Lin School of Medicine, Department of Physiology, National University of Singapore, Singapore 117597
* Authors contributed equally
Background: Tumorigenesis is a complex process of accumulated alteration in function of multiple genes and pathways. Wnt signalling pathway is involved in various differentiation events during embryonic development and is conserved in various species.
Objective: A multicentre collaborative initiative is undertaken to study the occurrence, prognosis and molecular mechanism of HNSCC (Head and Neck Squamous Cell Carcinoma) which is highly prevalent in eastern parts of India. From a large cohort of HNSCC tissue repository, 67 cases were selected for multi-parametric investigation.
Results: 67 cases showed stable β-catenin expression. We have seen correlation, if any, of the transcription factor - β-catenin, telomere maintenance and shelterin complex proteins - TRF2, Rap1 and hTert with respect to tumor differentiation and telomere dysfunction. Immunohistochemistry of β-catenin protein showed stable and high expression in tumor when compared to stroma. MDSCC (Moderately Differentiated Squamous cell carcinoma) cases expressed nuclear expression of β-catenin in invasive fronts and showed increased genomic instability. Higher frequency of Anaphase bridges was observed ranging from <3% in normal cut margin to 13% in WDSCC (Well differentiated squamous cell carcinoma) and 18% in MDSCC (Moderately differentiated Squamous cell carcinoma). There was significant decrease in telomere length in MDSCC (<4) when compared to the normal cut margin samples (<7). Quantitative Real Time-PCR confirmed a significant correlationship between stable β-catenin expression and poor clinical and pathological outcome.
Conclusion: The Stabilisation and accumulation of β-catenin was significant and correlated well with de-differentiation process as well as prognosis and therapy outcome of the patients in the cohort. Expression status of molecular markers such as β-catenin, hTert, TRF2 and RAP1 correlate significantly with the process of tumorigenesis and prognosis and may play a role in therapeutic management of Head and neck patients.
Keywords: HNSCC, Genomic instability, Wnt/β-catenin, Dedifferentiation, MDSCC, WDSCC.