Bundeswehr Institute of Radiobiology, D‑80937 Munich, Germany.
Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, D‑89081 Ulm, Germany.
Int J Mol Med. 2020 Nov;46(5):1733-1742. doi: 10.3892/ijmm.2020.4718. Epub 2020 Sep 2.
Radiotherapy is a major treatment option for head and neck squamous cell carcinoma (HNSCC). However, the success of radiotherapy is limited by tumor cell resistance to ionizing radiation (IR). Clinical studies have demonstrated an overall improved prognosis and higher susceptibility to radiotherapy of high‑risk human papillomavirus (HPV)‑associated HNSCC compared with classic HNSCC, as well as worse overall survival for male HNSCC patients. Overexpression of heterogeneous nuclear ribonucleoprotein (hnRNP) K has been associated with resistance to radiotherapy in melanoma and colorectal carcinoma. The aim of the present study was to analyze the impact of hnRNP K expression on the aggressiveness and radioresistance of HNSCC with respect to patient sex and HPV status. Immunohistochemical staining of HNSCC tissue specimens revealed elevated hnRNP K levels compared with those in the non‑neoplastic epithelium. Cytoplasmic hnRNP K accumulation was associated with advanced tumor stage and male sex. Exposure of HNSCC cells to IR was followed by rapid upregulation of hnRNP K at the protein level, along with re‑localization from the tumor cell nucleus to the cytoplasm. siRNA‑based knockdown of hnRNP K induced apoptosis and abolished tumor formation after xenotransplantation of HNSCC cells onto the chick egg chorioallantoic membrane (CAM). The observed effects were independent of the respective HPV status of the cell lines. These results indicated a tumorigenic and anti‑apoptotic role of hnRNP K in HNSCC, which appeared to be enhanced in male patients and contributed to the radioresistance of these tumors. However, the radioprotective effects of hnRNP K were found to be independent of the tumor's HPV status.
放射治疗是头颈部鳞状细胞癌（HNSCC）的主要治疗选择。然而，肿瘤细胞对电离辐射（IR）的抵抗限制了放射治疗的成功。临床研究表明，与经典 HNSCC 相比，高危型人乳头瘤病毒（HPV）相关 HNSCC 的总体预后改善和对放射治疗的敏感性更高，以及男性 HNSCC 患者的总体生存率更差。异质性核核糖核蛋白 K（hnRNP K）的过表达与黑色素瘤和结直肠癌对放射治疗的抵抗有关。本研究旨在分析 hnRNP K 表达对 HNSCC 侵袭性和放射抵抗性的影响，同时考虑患者性别和 HPV 状态。HNSCC 组织标本的免疫组织化学染色显示，hnRNP K 水平高于非肿瘤上皮。细胞质 hnRNP K 积累与肿瘤晚期和男性有关。HNSCC 细胞暴露于 IR 后，hnRNP K 蛋白水平迅速上调，并从肿瘤细胞核重新定位到细胞质。hnRNP K 的 siRNA 敲低诱导了 HNSCC 细胞凋亡，并在将 HNSCC 细胞异种移植到鸡胚尿囊膜（CAM）上后消除了肿瘤形成。观察到的效果与细胞系各自的 HPV 状态无关。这些结果表明 hnRNP K 在 HNSCC 中具有致癌和抗凋亡作用，在男性患者中似乎增强，并有助于这些肿瘤的放射抵抗性。然而，hnRNP K 的放射保护作用被发现与肿瘤的 HPV 状态无关。
