Molecular Interplays Between Cell Invasion and Radioresistance That Lead to Poor Prognosis in Head-Neck Cancer

Abstract

BackgroundCancer metastasis and recurrence after radiotherapy are the significant causes of poor prognosis in head-neck cancer (HNC). Clinically, it is commonly found that patients with either condition may accompany the outcome of the other. We hypothesized that HNC cells might exhibit a cross-phenotypic attribute between cell invasion and radioresistance. To discover effective biomarkers for the intervention of aggressive cancer at one time, the potential molecules that interplay between these two phenotypes were investigated.Materials and MethodsThree isogenic HNC cell sublines with high invasion or radioresistance properties were established. Transcriptomic and bioinformatic methods were used to globally assess the phenotypic-specific genes, functional pathways, and co-regulatory hub molecules. The associations of gene expressions with patient survival were analyzed by Kaplan-Meier plotter, a web-based tool, using the HNSCC dataset (n=500). The molecular and cellular techniques, including RT-qPCR, flow cytometry, cell invasion assay, and clonogenic survival assay, were applied.ResultsThe phenotypic crosstalk between cell invasion and radioresistance was validated, as shown by the existence of mutual properties in each HNC subline. A total of 695 genes was identified in associations with these two phenotypes, including 349 upregulated and 346 downregulated in HNC cells. The focal adhesion mechanism showed the most significant pathway to co-regulate these functions. In the analysis of 20 up-regulatory genes, a general portrait of correlative expression was found between these phenotypic cells (r=0.513, p=0.021), and nine molecules exhibited significant associations with poor prognosis in HNC patients (HR>1, p<0.050). Three hub genes were identified (ITGA6, TGFB1, and NDRG1) that represented a signature of interplayed molecules contributing to cell invasion, radioresistance and leading to poor prognosis. The ITGA6 was demonstrated as a prominent biomarker. The expression of ITGA6 correlated with the levels of several extracellular and apoptotic/anti-apoptotic molecules. Functionally, silencing ITGA6 suppressed cell migration, invasion, and attenuated radioresistance in HNC cells.ConclusionsA panel of interplay molecules was identified that contribute to cell invasion and radioresistance, leading to poor prognosis. These panel molecules, such as ITGA6, may serve as predictive markers of radioresistance, prognostic markers of metastasis, and molecular therapeutic targets for refractory HNC.

miR‐186‐5p inhibits the progression of oral squamous cell carcinoma by targeting ITGA6 to impair the activity of the PI3K/AKT pathway

“…[11][12][13] In addition, ITGA6 silencing largely represses the cell migration/invasion and enhances radiosensitivity in head and neck cancer. 28 In agreement with these findings, our study found that ITGA6 upregulation aggravated OSCC cell proliferation and migration, and enhanced the activity of the PI3K/AKT pathway. However, the reintroduction of miR-186-5p strongly abolished these effects, suggesting that miR-186-5p suppresses the expression and function of ITGA6.…”

“…ITGA6 is also upregulated in other malignancies, including gall bladder, pancreatic, and lung cancers, and ITGA6 overexpression is associated with cancer cell invasion and metastasis, and poor prognosis in patients 11‐13 . In addition, ITGA6 silencing largely represses the cell migration/invasion and enhances radiosensitivity in head and neck cancer 28 . In agreement with these findings, our study found that ITGA6 upregulation aggravated OSCC cell proliferation and migration, and enhanced the activity of the PI3K/AKT pathway.…”

MYH9 Facilitates Cell Invasion and Radioresistance in Head and Neck Cancer via Modulation of Cellular ROS Levels by Activating the MAPK-Nrf2-GCLC Pathway

“…The specific short hairpin RNA (shRNA) plasmids were constructed similarly as previously described [ 9 ]. In brief, approximately 22 oligonucleotide sense and short antisense hairpin (sh) oligonucleotides were designed to complement the gene-specific mRNA sequence.…”

“…Recently, an association between cell invasion and radioresistance has been demonstrated. These two malignant attributes share phenotypic crosstalk, and several molecules with both functions have been identified [ 9 ]. The molecules participating in these roles may be crucial to the pathological mechanism of HNC.…”

Targeted Profiling of Epitranscriptomic Reader, Writer, and Eraser Proteins Accompanied with Radioresistance in Breast Cancer Cells

“…Additionally, radioresistant breast cancer cells exhibit increased metastatic potential, and breast cancer distant metastasis was shown to promote resistance to radiation therapy . Based on the observed co-occurrence between metastasis and radioresistance, several reports interrogated their cross-regulation and revealed several common pathways, including PI3K/AKT/mTOR, MAPK, Wnt/β-catenin, NF-κB, EMT, and reactive oxygen species scavenging. − …”