Relationship between the Endogenous Hypoxic Markers Hypoxia Inducible Factor-1α, Carbonic Anhydrase IX, and Epithelial Mesenchymal Transition Regulator TWIST Expression in Non-small Cell Lung Cancer

Abstract

Background :The epithelial mesenchymal transition (EMT) is intimately associated with tumor hypoxia. The present study was conducted to investigate the immunohistochemical relationship between hypoxic and EMT-related molecules in non-small cell lung carcinoma (NSCLC). Methods : Immunohistochemical staining for hypoxia inducible factor (HIF)-1a, carbonic anhydrase (CA) IX, TWIST, and E-cadherin proteins was performed in 146 cases of NSCLC (80 cases of adenocarcinoma and 66 cases of squamous cell carcinoma) using tissue microarray blocks. Results : HIF-1a, TWIST, CA IX, and E-cadherin were expressed in 58 (40%), 90 (62%), 82 (56%), and 36 (25%) of 146 NSCLC cases, respectively. TWIST expression was positively correlated with HIF-1a expression (p = 0.03) and inversely correlated with E-cadherin expression (p < 0.01). TWIST and CA IX expression were not significantly interrelated, but each showed a relationship with histological tumor grade. However, the expression of these molecules had no significant effect on clinical staging or patient survival. Conclusions : Although TWIST expression was correlated positively with HIF-1a expression and inversely correlated with E-cadherin, HIF-1a expression was not associated with E-cadherin expression. However, considering the relationship between HIF-1a and TWIST expression, further studies should be performed to demonstrate the role of hypoxia-induced EMT in NSCLC.

Clinicopathological and prognostic significance of Twist overexpression in NSCLC

“…However, the prognostic value of Twist in lung cancer remains controversial. Some studies [ 24 – 26 ] have suggested that the expression of Twist might not predict the survival of NSCLC, while the other researches [ 27 – 30 ] have indicated a specific correlation between Twist expression and patient prognosis. Besides, the research of Hung et al [ 31 ] suggested Twist was associated with a shorter overall survival (OS), whereas the overexpression of Twist did not influence recurrence-free survival (RFS).…”

The Role of TWIST in Ovarian Epithelial Cancers

“…EMT is triggered by a set of stimuli, which include hypoxia and growth factors, and tumor stromal cell interactions with transcription factors such as TWIST, SNAI1, SLUG, and ZWB1 4. TWIST overexpression has also been identified in various kinds of epithelial tumors and plays a distinct role in tumor progression via the loss of E-cadherin expression 6,7,8,9,10,11,12,13,14,15,16…”

“…Some studies have identified that reduced E-cadherin expression is associated with more aggressive epithelial tumors. 9 , 12 , 17 , 21 TWIST binds the E-cadherin promoter and inhibits E-cadherin transcription levels, which modulate EMT in cancer progression. An inverse correlation between TWIST upregulation and E-cadherin downregulation was also observed in several types of malignancies.…”

“…HIF1α and HIF1α-regulated genes also promote EMT, a critical step in metastasis. Co-expression of HIF1α and TWIST has been shown, and could be used as a prognostic marker in cancer patients 12,20,21…”

“… 5 The role of TWIST proteins in cancer has been investigated over the course of the last decade. It has been found that TWIST is a central player in the EMT of many cancers, 6 including breast, 7 ovarian, 8 , 9 endometrial, 10 bladder, 11 lung, 12 gastric, 13 pancreatic, 14 prostate, 11 thyroid, 15 and head and neck squamous cell carcinomas (HNSCC). 16 In all cancer types, the expression of TWIST is associated with poor prognosis, and high-grade, invasive, and metastatic lesions.…”