Widespread expression of Sonic hedgehog (Shh) and Nrf2 in patients treated with cisplatin predicts outcome in resected tumors and are potential therapeutic targets for HPV-negative head and neck cancer

Abu Shadat M Noman; Rashed R Parag; Muhammad I Rashid; Mohammad Z Rahman; Ali A Chowdhury; Afrin Sultana; Chandsultana Jerin; Ayesha Siddiqua; Lutfur Rahman; Afsana Shirin; Junayed Nayeem; Reaz Mahmud; Sonam Akther; Rajib K Shil; Ikram Hossain; Sharmin Alam; Arfina Chowdhury; Shabnam B Basher; Abul Hasan; Shammy Bithy; Jannatul Aklima; Mizanur Rahman; Nabila Chowdhury; Tahmina Banu; Bedri Karakas; Herman Yeger; Walid A Farhat; Syed S Islam

doi:10.1177/1758835920911229

Widespread expression of Sonic hedgehog (Shh) and Nrf2 in patients treated with cisplatin predicts outcome in resected tumors and are potential therapeutic targets for HPV-negative head and neck cancer

Ther Adv Med Oncol. 2020 Mar 13:12:1758835920911229. doi: 10.1177/1758835920911229. eCollection 2020.

Authors

Abu Shadat M Noman¹, Rashed R Parag¹, Muhammad I Rashid¹, Mohammad Z Rahman², Ali A Chowdhury³, Afrin Sultana¹, Chandsultana Jerin¹, Ayesha Siddiqua¹, Lutfur Rahman¹, Afsana Shirin¹, Junayed Nayeem¹, Reaz Mahmud¹, Sonam Akther¹, Rajib K Shil¹, Ikram Hossain¹, Sharmin Alam¹, Arfina Chowdhury¹, Shabnam B Basher¹, Abul Hasan¹, Shammy Bithy¹, Jannatul Aklima¹, Mizanur Rahman¹, Nabila Chowdhury¹, Tahmina Banu⁴, Bedri Karakas⁵, Herman Yeger⁶, Walid A Farhat⁷, Syed S Islam⁸

Affiliations

¹ Department of Biochemistry and Molecular Biology, The University of Chittagong, Chittagong, Bangladesh.
² Department of Pathology, Chittagong Medical College and Hospital, Chittagong, Bangladesh.
³ Department of Radiotherapy, Chittagong Medical College and Hospital, Chittagong, Bangladesh.
⁴ Chittagong Research Institute of Children Surgery, Chittagong, Bangladesh.
⁵ Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
⁶ Developmental and Stem Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁸ Department of Molecular Oncology, Cancer Biology and Experimental Therapeutics, King Faisal Specialist Hospital and Research Centre, School of Medicine, Alfaisal University, Thakassussi Street, Riyadh, 11211, Saudi Arabia.

Abstract

Background: Sonic hedgehog (Shh) and Nrf2 play a critical role in chemotherapeutic resistance. These two genes have been found to be dysregulated in head and neck squamous cell carcinomas (HNSCC). The purpose of this study was to analyze the expression, function and clinical prognostic relationship of Shh and Nrf2 in HNSCC in the context of therapeutic resistance and cancer stem cells (CSCs).

Methods: We analyzed a cohort of patients with HNSCC to identify potential therapeutic biomarkers correlating with overall survival (OS) as well as disease-free survival (DFS) from our own data and validated these results using The Cancer Genome Atlas dataset. Expression of Shh and Nrf2 was knocked down by siRNA and cell growth, sphere growth and chemotherapeutic resistance were evaluated.

Results: Widespread abundant expression of Shh and Nrf2 proteins were associated with shorter OS and DFS. The combination of Shh and Nrf2 expression levels was found to be a significant predictor of patient DFS. The tumor stromal index was correlated with Shh expression and inversely associated with shorter OS and DFS. Inhibition of Shh by siRNA or cyclopamine resulted in the attenuation of resistant CSC self-renewal, invasion, clonogenic growth and re-sensitization to the chemotherapeutic agents. Concomitant upregulation of Shh and Nrf2 proved to be an independent predictor of poor OS and DFS in patients with HNSCC.

Conclusions: These findings suggest that Shh and Nrf2 could serve as therapeutic targets as well as promising dual prognostic therapeutic biomarkers for HNSCC.

Keywords: HNSCC; Nrf2; Shh; cisplatin; disease-free survival; overall survival.