Abstract
Background: Serine Threonine Kinase 11 (STK11), also known as LKB1, is a tumor suppressor gene that regulates several biological processes such as apoptosis, energetic metabolism, proliferation, invasion, and migration. During malignant progression, different types of cancer inhibit STK11 function by mutation or epigenetic inactivation. In Head and Neck Cancer, it is unclear what mechanism is involved in decreasing STK11 levels. Thus, the present work aims to determine whether STK11 expression might be regulated through epigenetic or post-translational mechanisms. Methods: Expression levels and methylation status for STK11 were analyzed in 59 cases of head and neck cancer and 10 healthy tissue counterparts. Afterward, we sought to identify candidate miRNAs exerting post-transcriptional regulation of STK11. Then, we assessed a luciferase gene reporter assay to know if miRNAs directly target STK11 mRNA. The expression levels of the clinical significance of mir-100-3p, -5p, and STK11 in 495 HNC specimens obtained from the TCGA database were further analyzed. Finally, the Kaplan–Meier method was used to estimate the prognostic significance of the miRNAs for Overall Survival, and survival curves were compared through the log-rank test. Results: STK11 was under-expressed, and its promoter region was demethylated or partially methylated. miR-17-5p, miR-106a-5p, miR-100-3p, and miR-100-5p could be negative regulators of STK11. Our experimental data suggested evidence that miR-100-3p and -5p were over-expressed in analyzed tumor patient samples. Luciferase gene reporter assay experiments showed that miR-100-3p targets and down-regulates STK11 mRNA directly. With respect to overall survival, STK11 expression level was significant for predicting clinical outcomes. Conclusion: This is, to our knowledge, the first report of miR-100-3p targeting STK11 in HNC. Together, these findings may support the importance of regulation of STK11 through post-transcriptional regulation in HNC and the possible contribution to the carcinogenesis process in this neoplasia.
Highlights
Head and Neck cancer (HNC) is the sixth most common cancer worldwide, and approximately200,000 annual deaths are attributed to this type of cancer [1]
We searched public databases for microRNAs that could interact with the 30 -UTR of Serine Threonine Kinase 11 (STK11); thereby, we found that miR-17-5p, miR-106a-5p and miR-100-3p interact with the 3′‐UTR of STK11; thereby, we found that miR‐17‐5p, miR‐106a‐5p and miR‐100‐3p and -5p might be implicated in STK11 down-regulation in HNC, since STK11 could be a putative and ‐5p might be implicated in STK11 down‐regulation in HNC, since STK11 could be a putative target
We showed a down-regulation of STK11 expression in HNC tumors, compared to their normal counterparts
Summary
Head and Neck cancer (HNC) is the sixth most common cancer worldwide, and approximately200,000 annual deaths are attributed to this type of cancer [1]. It has been established that tobacco, alcohol, and their synergistic effect are strong risk factors for HNC development [4,5]; the presence of high-risk human papillomaviruses (HPVs) has been reported, and they are considered to be etiological agents for some of these cancers [6]. As previously mentioned, this malignancy is determined by several alterations and risk factors, which in combination lead to greater tumor heterogeneity and pose a complex challenge for treatment [7]. The present work aims to determine whether STK11 expression might be regulated through epigenetic or post-translational mechanisms
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