Question

How can you tell if the gene was highly expressed in cancer cells compared to normal cells? What about the other way around?

Answer 1

ANS :The accumulation of genetic and epigenetic alterations in cancer cells endows them with unwanted proliferative and metastatic potential. However these alterations can also handicap cancer cells with unique vulnerabilities such that it is possible to identify particular genes whose function is more critical for the viability of cancer cells than for normal cells. Mutations in such genes are formally synthetic lethal with the genetic and epigenetic alterations present in cancer cells. Proteins encoded by such synthetic lethal genes identify molecular targets for therapy since antagonizing their function will be more toxic to cancer cells than to normal cells, thus yielding superior therapeutic index. The inability to perform synthetic lethal screens in cultured human cells has limited the number of genes identified whose inactivation is uniquely toxic to human cancer cells, although this is likely to change with the advent of high throughput gene silencing technologies.

The evolutionarily conserved TREX complex physically couples transcription, mRNP biogenesis, RNA processing, and RNA export for a subset of genes. HPR1 encodes an essential component of the S. cerevisiae TREX complex. HPR1 loss compromises transcriptional elongation, nuclear RNA export, and genome stability. Yet, HPR1 is not required for yeast viability. Thoc1 is the recently discovered human functional orthologue of HPR1. Thoc1 is expressed at higher levels in breast cancer than in normal epithelia, and expression levels correlate with tumor size and metastatic potential. Depletion of Thoc1 protein (pThoc1) in human cancer cell lines compromises cell proliferation. It is currently unclear whether Thoc1 is essential for all mammalian cells, or whether cancer cells may differ from normal cells in their dependence on Thoc1. To address this issue, we have compared the requirement for Thoc1 in the proliferation and survival of isogenic normal and oncogene transformed cells. Neoplastic cells rapidly lose viability via apoptotic cell death upon depletion of pThoc1. Induction of apoptotic cell death is coincident with increased DNA damage as indicated by the appearance of phosphorylated histone H2AX. In contrast, the viability of normal cells is largely unaffected by pThoc1 loss. Normal cells lacking Thoc1 cannot be transformed by forced expression of E1A and Ha-ras, suggesting that Thoc1 may be important for neoplastic transformation. In sum, our data are consistent with the hypothesis that cancer cells require higher levels of pThoc1 for survival than normal cells. If true, pThoc1 may provide a novel molecular target for cancer therapy.