Abstract
TMEM45A is a transmembrane protein involved in tumor progression and cancer resistance to chemotherapeutic agents in hypoxic condition. It is correlated to a low breast cancer patient overall survival. However, little is known about this protein, in particular the mechanisms by which TMEM45A modulates cancer cell chemosensitivity. In this work, the messenger RNA expression of TMEM45A was assessed in head and neck squamous cell carcinoma (HNSCC) and renal cell carcinoma (RCC) biopsies. TMEM45A was upregulated in patients diagnosed for head and neck or renal cancer. Then, the implication of this protein in cisplatin sensitivity was explored in SQD9 and RCC4 + pVHL cells. TMEM45A inactivation decreased cell proliferation and modulated cell responses to cisplatin. Indeed, TMEM45A inactivation increased the sensitivity of SQD9 cells to cisplatin, whereas it rendered RCC4 + pVHL cells resistant to this anticancer agent. Through RNA-sequencing analysis, we identified several deregulated pathways that indicated that the impact on cisplatin sensitivity may be associated to the inhibition of DNA damage repair and to UPR pathway activation. This study demonstrated, for the first time, an anti or a pro-apoptotic role of this protein depending on the cancer type and highlighted the role of TMEM45A in modulating patient responses to treatment.
Highlights
Renal cell carcinoma (RCC) and head and neck squamous cell carcinoma (HNSCC) constitute two of the ten most common cancers[1,2]
TMEM45A transcript was upregulated in tumor tissues compared to healthy tissues in 86% (19/22) and 76% (19/ 25) of HNSCC and clear cell RCC (ccRCC) samples respectively (Fig. 1a, b)
TCGA analysis showed that TMEM45A expression was significantly higher in HNSCC and ccRCC human tumors than in corresponding healthy tissues (Fig. 1c)
Summary
Renal cell carcinoma (RCC) and head and neck squamous cell carcinoma (HNSCC) constitute two of the ten most common cancers[1,2]. International Agency for Research on Cancer recorded >350,000 new cases of HNSCC worldwide in 2018, with 25% of oral cancer being HPV-positive[3]. The current standard treatments for this disease are surgery, radiotherapy, and chemotherapy. The four most extensively used agents are methotrexate, cisplatin, 5-fluorouracil (5-FU), and bleomycin. Significant advances have been made in combined modality therapies but the majority of patients who present advanced disease relapse still develop metastases and only qualify for palliative treatment[4]. Human RCCs are classified in subtypes with the most common being clear cell RCC (ccRCC), which represents
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