Crm1 knockdown by specific small interfering RNA reduces cell proliferation and induces apoptosis in head and neck cancer cell lines

Abstract

2014). In most cases of HNSCC, only 51% of short-term malignancies and only 10.5% of long-term malignancies could be detected even with advanced investigations. Fiveyear survival rates are 51% in short-term malignancies and 28% in long-term malignancies (Jemal et al., 2009).The underlying mechanism of HNSCC invasion and metastasis is a multistep process characterized by multiple genetic and molecular changes (Wilken et al., 2011). However, not all of the underlying molecular mechanisms of HNSCC pathology are clear. Additionally, despite the standard therapies, including radiation, surgery, and/or chemotherapy, there has been no significant change in the survival rate within the last 20-30 years, and the mortality rate for HNSCC is still high (Jemal et al., 2009). Therefore, it is very important to investigate new candidate molecules for the diagnosis, follow-up, and control of HNSCC. Moreover, the investigation of potential target molecules that may be responsible for the HNSCC pathogenesis is crucial for the development of new clinical therapeutic approaches.Chromosome region maintenance 1 (Crm1), a member of the cytoplasm-nucleus transport receptor family known as the karyopherins, is an important nuclear export protein in mammals that facilitates the transport of various classes of RNAs, proteins, and other macromolecules from the nuclear membrane to the cytoplasm, and it helps maintain their appropriate subcellular localization (Kudo et al., 1997;Nguyen et al., 2012;Turner et al., 2012). Crm1 has a broad range of substrates and recognizes numerous cargo proteins, which are rich in nuclear export signal (NES) sequences, including tumor suppressor proteins such as p53, p27, and p21. These tumor suppressor proteins carry NES sequences rich in leucine amino acids and Abstract: Head and neck squamous cell carcinoma (HNSCC) is the most common and most aggressive type of head and neck cancer. Current approaches for the treatment of HNSCC are not sufficient to increase the patient survival or to reduce the high recurrence rate. Consequently, there is a need to explore the molecular characteristics of this cancer in order to discover potential therapeutic target molecules. The overexpression of chromosome region maintenance 1 (Crm1), responsible for the transport of different classes of macromolecules from the nuclear membrane to the cytoplasm, in various cancer cells has made it an attractive target molecule in cancer research. It has been reported that transcription factors, which are the target cargo proteins of Crm1, have critical roles in regulating intracellular processes via their expression levels and functions, which in turn are regulated by the cell cycle and signaling proteins. Previous findings show that head and neck cancer cells overexpress Crm1 and that these cells become highly dependent on Crm1 function. The results of this study show that after decreasing Crm1 expression levels in HNSCC cells through either treatment with specific Crm1 RNA interference (siRNA) or the selective Crm1 inhibitor leptomyc...

Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response

“…Leptomycin B is an XPO1 antagonist molecule and has been previously validated to suppress tumorigenic properties in HNSCC cell lines. 50,51 Following an in-silico based genetic perturbation of XPO1, we observed a distinct reversal of baseline RNA velocity trajectories now extend from the LE to the TC. In fact all effective drugs (low IC50 values) consistently demonstrated RNA velocity patterns that opposed canonical differentiation patterns, and extended from the LE to the TC.…”

Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response

“…Alvocidib is a CDK inhibitor currently under investigation for its use in acute myeloid lymphoma (AML) 75 , which demonstrated above average outgoing LE and incoming TC transitory signals in our analysis. As CDK inhibitors have been previously associated with promising results in OSCC cell lines 76,77 , Alvocidib may be a promising candidate for further research 78,79 . Importantly, the results of our perturbation analysis illustrate how spatial transcriptional profiles may be leveraged to assess drug efficacy in-silico and demonstrate that the tumor LE is a credible drug target.…”

Identification of fatty acid-related subtypes, the establishment of a prognostic signature, and immune infiltration characteristics in lung adenocarcinoma

“…Among the seven candidate drugs, leptomycin B is the first generation of chromosome region maintenance (CRM) inhibitor. The anti-cancer effect of leptomycin B has been detected in a variety of cancer cell lines, such as LC [ 59 ] and head and neck cancer [ 60 ]. In addition, leptomycin B combined with other drugs can enhance the sensitivity of cancer cells to chemotherapy drugs [ 61 , 62 ].…”