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Colorectal cancer（CRC） is the second most common cancer in women and the third most common in men globally. CRC arises from one or a combination of chromosomal instability, Cp G island methylator phenotype, and microsatellite instability. Genetic instability is usually caused by aneuploidy and loss of heterozygosity. Mutations in the tumor suppressor or cell cycle genes may also lead to cellular transformation. Similarly, epigenetic and/or genetic alterations resulting in impaired cellular pathways, such as DNA repair mechanism, may lead to microsatellite instability and mutator phenotype. Non-coding RNAs, more importantly micro RNAs and long non-coding RNAs have also been implicated at various CRC stages. Understanding the specific mechanisms of tumorigenesis and the underlying genetic and epigenetic traits is critical in comprehending the disease phenotype. This paper reviews these mechanisms along with the roles of various non-coding RNAs in CRCs.

Tumor suppressor PTEN regulates cellular activities and controls genome stability through multiple mechanisms. In this study, we report that PTEN is necessary for the protection of DNA replication forks against replication stress. We show that deletion of PTEN leads to replication fork collapse and chromosomal instability upon fork stalling following nucleotide depletion induced by hydroxyurea. PTEN is physically associated with replication protein A 1 （RPA1） via the RPA1 C-terminal domain. STORM and iPOND reveal that PTEN is localized at replication sites and promotes RPA1 accumulation on replication forks. PTEN recruits the deubiquitinase OTUB1 to mediate RPA1 deubiquitination. RPA1 deletion confers a phenotype like that observed in PTEN knockout cells with stalling of rep- lication forks. Expression of PTEN and RPA1 shows strong correlation in colorectal cancer. Heterozygous disruption of RPA1 promotes tumorigenesis in mice. These results demonstrate that PTEN is essential for DNA replication fork protection. We propose that RPA1 is a target of PTEN function in fork protection and that PTEN maintains genome stability through regulation of DNA replication.

DNA double-strand breaks （DSBs） are traditionally associated with cancer through their abilities to cause chro- mosomal instabilities or gene mutations. Here we report a new class of self-inflicted DNA DSBs that can drive tumor growth irrespective of their effects on genomic stability. We discover a mechanism through which cancer cells cause DSBs in their own genome spontaneously independent of reactive oxygen species or replication stress. In this mech- anism, low-level cytochrome c leakage from the mitochondria leads to sublethal activation of apoptotic caspases and nucleases, which causes DNA DSBs. In response to these spontaneous DNA DSBs, ATM, a key factor involved in DNA damage response, is constitutively activated. Activated ATM leads to activation of transcription factors NF- KB and STAT3, known drivers of tumor growth. Moreover, self-inflicted DNA DSB formation and ATM activation are important in sustaining the sternness of patient-derived glioma cells. In human tumor tissues, elevated levels of activated ATM correlate with poor patient survival. Self-inflicted DNA DSBs therefore are functionally important for maintaining the malignancy of cancer cells.

Understanding of the mechanism of colorectal carcinogenesis has been gaining momentum for some years on account of its high incidence and impact on the lives of individuals affected. Different genetic abnormalities have been found in colorectal cancers from different sites. For example, proximal colon cancer is usually related to the nucleotide instability pathway, as microsatellite instability （MSI）. However, distal colon cancer is usually associated with specific chromosomal instability （CIN）. The development of cancer at the rectum, though similar to that at the colon, displays its own unique features. These differences might be partially attributed to different embryological development and physiological circumstances. Environmental factors such as diet and alcohol intake also differ in their role in the development of tumors in the three segments, proximal colon, distal colon, and rectum. ＂Proximal shift＂ of colon cancer has been known for some time, and survival rates of colorectal cancer are higher when rectal cancers are excluded, both of which emphasize the three different segments of coloreetal cancer and their different properties. Meanwhile, colonic and rectal cancers are distinctive therapeutic entities. The concept of three entities of coloreetal cancer may be important in designing clinical trails or therapeutic strategies. However, the dispute about the inconsistency of data coneerning the site-specific mechanism of eolorectal carcinoma does exist, and more evidence about molecular events of carcinogenesis and targeted therapy needs to be collected to definitely confirm the conception.