Abstract
Despite chemoradiotherapy being one of the most important modalities in advanced cervical cancer, there is a lack of both usable biomarkers to predict treatment outcome and of knowledge about the mechanism of refractoriness to the therapy. Here we identified a transcriptional factor Single-minded homolog 2 (SIM2) as an independent predictive biomarker for uterine cervical squamous cell carcinoma (CvSCC). The retrospective study showed that high expression level of SIM2 was correlated to good survival in CvSCC patients. SIM2 knockdown in CvSCC cell lines showed resistance to hypoxia with increased expression of HIF1A and its target genes. Loss of SIM2 also caused growth promotion, resistance to ROS, and radiation in 3D culture. Furthermore, SIM2 knockdown suppressed tumor growth with increased HIF-1α expression and angiogenesis in vivo. On the other hand, SIM2 long isoform (SIM2l)-overexpressed cells had contrary results, indicating the long isoform plays a key role for maintenance of these phenotypes. These data indicated that SIM2l has a potential to be precision medicine for CvSCC patients and that anti-angiogenesis therapy might be usable for SIM2lLow poor survivors.
Highlights
Among females, cervical cancer is one of the four most common malignancies, accounting for 528,000 new cases in 2012 and the fourth most common cause of cancer deaths worldwide, with an estimated 266,000 deaths in 2012 which are account for 7.5% of gynecological cancers[1]
Single-minded homolog 2 (SIM2) has been reported to be over-expressed in prostate cancer[20,21], whereas its expression is decreased in esophageal squamous cell carcinoma compared to normal tissue[26], indicating SIM2 regulation is distinct by cancer types
We evaluated the relationship between SIM2 mRNA expression and clinical outcome using another The Cancer Genome Atlas (TCGA) dataset including RNA sequencing data of 248 cervical squamous cell carcinoma (CvSCC) patients
Summary
Cervical cancer is one of the four most common malignancies, accounting for 528,000 new cases in 2012 and the fourth most common cause of cancer deaths worldwide, with an estimated 266,000 deaths in 2012 which are account for 7.5% of gynecological cancers[1]. In prostate cancer, various studies have reported an increased expression of SIM2 and its contribution to tumor progression and aggressiveness[20,21]. In contrast to the oncogenic function mentioned above, SIM2s behaves as a tumor suppressor, which inhibits epithelial-mesenchymal transition and represses growth and invasion in breast cancer[23,24,25]. In addition to these facts that SIM2s functions differently by cancer types, the authentic function of SIM2l is still missing pieces of the puzzle. We discovered SIM2 expression is an independent predictive biomarker for CvSCC patients who received chemoradiotherapy. A series of gene knockdown and overexpression experiments revealed that SIM2l acts as a tumor suppressor gene via transcriptional suppression of HIF1A and decreased radiation resistance and tumor growth in CvSCC
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