Key result
Weak Midkine (MDK) expression was independently associated with improved overall survival compared to strong expression in patients with resectable head and neck squamous cell carcinoma (adjusted HR 0.475).
Why the study?
It was unclear whether Midkine influences the renin-angiotensin system pathway through angiotensin II type 1 receptor to contribute to poor prognosis in head and neck squamous cell carcinoma.
Does MDK and AT1R expression predict survival in patients with resectable head and neck squamous cell carcinoma?
Cohort (n=150)
No
Does MDK and AT1R expression predict survival in patients with resectable head and neck squamous cell carcinoma?
Hazard Ratio: 0.475 (95% CI 0.28–0.82)
p-value: p=0.007
MDK and AT1R expression are highly correlated and predict poor survival in resectable HNSCC, suggesting that AT1R blockade may be a potential therapeutic strategy to counteract MDK-mediated tumor progression.
MDK expression may stratify prognosis in resectable HNSCC but should not yet change practice; leaves open AT1R blockade as a therapeutic hypothesis.
BACKGROUND: Research studies have demonstrated that Midkine (MDK) can influence the expression and activity of Renin-angiotensin system (RAS) components. Angiotensin II is involved in tumor growth and angiogenesis in different cancers. We previously observed Angiotensin II receptor blockers (ARBs) improve the survival rates of patients with oral cancers. These findings have prompted us to investigate whether MDK can influence the RAS pathway, mainly through its association with angiotensin II type 1 receptor (AT1R), which contributes to the observed poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients. METHODS: MDK and AT1R expressions were examined in 150 HNSCC patients post-operation by immunohistochemical staining between 1 January 2010 and 31 December 2016. We tested the over-expression and silencing of MDK to evaluate the AT1R expression and functional biological assays in HNSCC cell lines HSC-3 and SAS. RESULTS: Positive expression of MDK is correlated with positive AT1R expression. MDK predicted poor NSCC patients' survival. Silencing MDK could suppress AT1R and pAKT expression and reduce the growth, migration, and invasion of HNSCC cells. ARB also inhibits MDK stimulating HNSCC cell proliferation. Overexpression of MDK could upregulate AT1R and pAKT. CONCLUSIONS: MDK is an independent prognostic factor of HNSCC post-operation, and AT1R regulates HNSCC cell growth, invasion, and migration. Positive MDK and AT1R expressions are highly correlated. Mechanistically, the interaction between MDK and AT1R is crucial for MDK-mediated cell viability, and inhibiting AT1R can effectively counteract or abolish these effects. Furthermore, MDK exerts a regulatory role in the expression of AT1R, as well as in the growth and motility of HNSCC cells. These findings highlight the involvement of the interaction between MDK, AT1R, and the pAkt signaling pathways in HNSCC cell viability growth.
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Chiu et al. (2023) conducted a cohort in Head and neck squamous cell carcinoma (HNSCC) (n=150). Weak Midkine (MDK) expression vs. Strong Midkine (MDK) expression was evaluated on Overall survival (HR 0.475, 95% CI 0.28-0.82, p=0.007). Weak Midkine (MDK) expression was independently associated with improved overall survival compared to strong expression in patients with resectable head and neck squamous cell carcinoma (adjusted HR 0.475).
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