The oncogenic role of microRNA-138 in undifferentiated nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is different from other head and neck squamous cell carcinomas and is closely related with Epstein-Barr virus infection. It is endemic in southern China and Southeast Asia, affecting between 20 and 30 per 100,000 populations. According to the World Health Organization (WHO) histological classification, there are three subtypes of NPC: WHO type 1 NPC is keratinizing squamous cell carcinoma; type 2 NPC is differentiated non-keratinizing carcinoma; type 3 NPC is undifferentiated non-keratinizing carcinoma. In southern China including Hong Kong, type 3 NPC (undifferentiated NPC) is dominant and constitutes over 90% of the total NPC. MicroRNA-138 (miR-138) is a small non-coding RNA which has been reported to be highly expressed in undifferentiated NPC. We hereby evaluated whether the miR-138 level could be used to differentiate NPC patients from the normal individuals and examine the potential oncogenic role in undifferentiated NPC cell line. To validate the hypothesis that miR-138 was an oncogenic microRNA, which is overexpressed in undifferentiated NPC patients, we first examined its expression level in nasopharyngeal tissues and peripheral blood. In our cohort, cancer tissues samples were collected from 42 primary NPC and 29 recurrent NPC patients. To evaluate the expression level in the cancer tissues, the miR-138 level was quantified by real-time quantitative polymerase chain reaction. For primary NPC, the expression level was compared with 29 normal nasopharyngeal epithelia. For recurrent NPC, the microRNA level was compared with the paired normal mucosa counterparts obtained from the same patients. In addition, plasma samples were also collected from 22 primary NPC, 21 recurrent NPC and 17 normal individuals. Our data suggested that there was no difference in the miR-138 expression level in primary NPC tissue and normal nasopharyngeal tissue from control. There was no difference in the circulating miR-138 levels in the primary NPC, recurrent NPC and normal control groups. The circulating miR-138 could not be used to differentiate NPC patients from the normal individuals. Further functional analysis on the undifferentiated NPC cell line HONE1 suggested that miR-138 overexpression could enhance NPC cell proliferation, migration and invasion in comparison with the mock control. With the use of high-throughput gene expression arrays, we observed that multiple cancer-related pathways were affected in miR-138 overexpressed NPC cells. Staining with Acridine orange (AO) and phosphorylated H2AX (γH2AX) showed that miR-138 overexpression is associated with an enhanced response to radiation. Our results are concordant with other similar studies suggested that miR-138 is an oncogenic microRNA which play an important part in the undifferentiated NPC tumorigenesis. Further studies, based on larger sample size, are warranted to explore the clinical use of this small RNA in diagnosis, prognosis and management of undifferentiated NPC.