Abstract
Objective: Ovarian cancer has the highest mortality among gynecological cancers. High-grade serous carcinoma (HGSC) is the most common histotype of ovarian cancer regardless of ethnicity, whereas clear cell carcinoma (CCC) is more common in East Asians than Caucasians. The elucidation of predominant signaling pathways in these cancers is the first step towards understanding their molecular mechanisms and developing their clinical management. Methods: RNA sequencing was performed for 27 clinical ovarian specimens from Japanese women. Principal component analysis (PCA) was conducted on the sequence data mapped on RefSeq with normalized read counts, and functional annotation analysis was performed on genes with substantial weights in PCA. Knockdown experiments were conducted on the selected genes on the basis of PCA. Results: Functional annotation analysis of PCA-defined genes showed predominant pathways, such as cell growth regulators and blood coagulators in CCC and transcription regulators in HGSC. Knockdown experiments showed that the inhibition of the calcium-dependent protein copine 8 (CPNE8) and the transcription factor basic helix-loop-helix family member e 41 (BHLHE41) repressed the proliferation of CCC- and HGSC-derived cells, respectively. Conclusions: This study identified CPNE8 and BHLHE41 as characteristic genes for CCC and HGSC, respectively. The systemic identification of differentially expressed genes in CCC and HGSC will provide useful information to understand transcriptomic differences in these ovarian cancers and to further develop potential diagnostic and therapeutic options for advanced disease.
Highlights
Ovarian cancer has the highest mortality in gynecological cancers and is responsible for the death of ~4500 women per year in Japan [1]
To visualize the relationships between the 6 cell carcinoma (CCC), 15 High-grade serous carcinoma (HGSC), and 6 normal tissues based on gene expression, we performed principal component analysis (PCA) based on the expression level represented by log2RPKM value for each RefSeq gene (Figure 1A)
The result indicated that the three groups, CCC, HGSC, and normal tissues, could be characterized by the first two principal components: the proportion of the variability regarding the first principal component (PC1) and the second principal component (PC2) was 18.5% and 11.0%, respectively (Figure 1B)
Summary
Ovarian cancer has the highest mortality in gynecological cancers and is responsible for the death of ~4500 women per year in Japan [1]. IGF signaling pathways are involved in tumor progression and drug resistance in ovarian cancer. High IGF2 expression in serous ovarian cancer is significantly associated with a shorter interval to disease progression and death and resistance to the chemotherapy drug Taxol [12,13,14]. Gene expression profiling implies that the overexpression of hepatocyte nuclear factor-1β (HNF-1β) and hypoxia-inducible factor 1 α (HIF-1α) is a key driver event in CCC [18,19] These findings suggest that different types of ovarian cancer develop along with different molecular pathways. Functional analysis of candidate genes predominantly expressed in CCC and HGSC revealed distinct signaling pathways in the two cancer histotypes, which would play roles in cancer cell proliferation
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