Abstract. Oral squamous cell carcinoma (OSCC) is a prevalent cancer worldwide. Let-7 family has been shown to function as a tumor suppressor through regulating multiple oncogenic signaling. Recent study reported that combined underexpression of miR-205 and let-7d showed negative correlation with the survival prognosis of head and neck cancer patients. However, the let-7d-involved mechanism in regulating OSCC is still unclear. In this study, we first demonstrated that let-7d expression was significantly decreased while Twist and Snail expression was increased in OSCC cancer cell lines and primary cultures as compared to normal human oral keratinocyte cells. To further investigate the role of let-7d in OSCC, we applied the SPONGE method to knock down let-7d in OECM-1 and two primary OSCC cell types. The results showed that knockdown of let-7d promote epithelialmesenchymal transition (EMT) traits and migratory/invasive capabilities in OSCC cells. Furthermore, down-expression of let-7d significantly activated Twist and Snail expressions and chemo-resistant abilities of OSCC cells. Notably, overexpression of let-7d effectively reversed the EMT phenotype, blocked migratory/invasive abilities, and further increased the chemosensitivity in oral cancer tumor initiating ALDH1 + cells. In sum, these results show that let-7d negatively modulates EMT expression and also plays a role in regulating chemo-resistant ability in oral cancer.
IntroductionHead and neck squamous cell carcinoma, including oral squamous cell carcinoma (OSCC), is the sixth most prevalent malignancy worldwide and accounts for approximately 8-10% of all cancers in Southeast Asia (1,2). The prognosis of OSCC remains dismal as more than 50% of the patients die of this disease or complications within 5 years under current therapies (2). To increase patient survival rate, investigations elucidating the mechanisms of tumorigenesis in OSCC are urgently needed (2). Some studies have suggested that subsets of cancer stem cells (CSC) or tumor initiating cells (TICs) are responsible for tumor progression as well as recurrence after conventional chemotherapy (3). However, there is lack of suitable markers for isolating the crucial subset of tumor cells that is capable of reforming new tumors in vivo and accounts for tumor relapse in OSCC, according to CSC hypothesis of tumorigenesis.MicroRNAs (miRNAs), highly conserved small RNA molecules that regulate gene expression, can act as cancer signatures, oncogenes or tumor suppressors (4). The ubiquitously expressed let-7/miR-98 family was one of the first mammalian miRNAs to be identified (5-8). Let-7 family members have been described as being down-regulated during cancer progression in various human cancers including lung, gastric, ovarian, colon cancer, leiomyoma and melanoma (5-13). Let-7d, a member of the let-7 family of miRNAs, has also been shown to act as tumor suppressor, most likely through targeting RAS (14) or high mobility group A2 (15). Let-7d regulates senescence of human cord blood-derived multipotent ste...