TMEM45A is essential for hypoxia-induced chemoresistance in breast and liver cancer cells

Abstract

BackgroundHypoxia is a common characteristic of solid tumors associated with reduced response to radio- and chemotherapy, therefore increasing the probability of tumor recurrence. The aim of this study was to identify new mechanisms responsible for hypoxia-induced resistance in breast cancer cells.MethodsMDA-MB-231 and HepG2 cells were incubated in the presence of taxol or etoposide respectively under normoxia and hypoxia and apoptosis was analysed. A whole transcriptome analysis was performed in order to identify genes whose expression profile was correlated with apoptosis. The effect of gene invalidation using siRNA was studied on drug-induced apoptosis.ResultsMDA-MB-231 cells incubated in the presence of taxol were protected from apoptosis and cell death by hypoxia. We demonstrated that TMEM45A expression was associated with taxol resistance. TMEM45A expression was increased both in MDA-MB-231 human breast cancer cells and in HepG2 human hepatoma cells in conditions where protection of cells against apoptosis induced by chemotherapeutic agents was observed, i.e. under hypoxia in the presence of taxol or etoposide. Moreover, this resistance was suppressed by siRNA-mediated silencing of TMEM45A. Kaplan Meier curve showed an association between high TMEM45A expression and poor prognostic in breast cancer patients. Finally, TMEM45 is highly expressed in normal differentiated keratinocytes both in vitro and in vivo, suggesting that this protein is involved in epithelial functions.ConclusionAltogether, our results unravel a new mechanism for taxol and etoposide resistance mediated by TMEM45A. High levels of TMEM45A expression in tumors may be indicative of potential resistance to cancer therapy, making TMEM45A an interesting biomarker for resistance.

Systematic Identification and Characterization of Novel Human Skin-Associated Genes Encoding Membrane and Secreted Proteins

“…Our observations suggest that GPR87, GPR115 and/or TMEM45A may have similar functions in skin cancers. Interestingly, TMEM45A expression in primary human keratinocytes is induced upon differentiation [58]. These findings are in line with the results of our immunohistochemical analyses, showing increased TMEM45A staining from the basal layers of the epidermis to the stratum corneum (Figure 5c).…”

“…Thus, this gene and its protein product may play a role in immunity in the skin. A recent study reported that TMEM45A is overexpressed in breast cancer and is associated with poor prognosis in these patients [58]. Conversely, TMEM45A suppression promotes the progression of ductal carcinoma in situ to invasive breast cancer [59].…”

High TMEM45A expression is correlated to epidermal keratinization

“…This study confirms that TMEM45A expression in human keratinocytes, although present in subconfluent undifferentiated keratinocytes, is upregulated during epidermal differentiation, either induced by culture confluence or enhancement of Ca 2+ concentration in medium, as previously published . It also demonstrates strong connection between TMEM45A expression and keratinization, in both epidermis in vivo or during reconstruction in culture, but also in Hassal bodies inside the thymus.…”

“…Subcellular localization and functions remain unknown. Recently, we briefly reported selective induction of TMEM45A expression in differentiating keratinocytes, as well as increased expression in normal human epidermis , data later confirmed by others . Finally, in an approach using keratinocytes fractions purified from normal epidermis, TMEM45A was reported as a differentiation‐associated gene, because of its significantly higher mRNA level in granular and cornified keratinocytes‐enriched fraction compared with its level in basal keratinocytes‐enriched fraction .…”

“…However, how alterations of TMEM45A expression are involved in diseases remains to be solved. In cancer cells, though, TMEM45A expression is implicated in resistance against drug‐induced apoptosis in hypoxic conditions by a still unknown mechanism . Conversely, it suppresses the progression of ductal carcinoma into invasive breast cancer, again by an unknown mechanism .…”