We also established a lack of correlation between MSI incidence and sequence conservation level or distance from genetic elements. Our data indicate that microsatellite length dependency should be taken into account when evaluating 39UTR MSI in MMR-deficient cells. This study also provides a screening strategy for novel functionally relevant 39UTR MSI events in human tumorigenesis.RB1CC1 acts oncogenic in promoting cell survival and migration by activating Wnt signaling, TNF-alpha-induced JNK activity, and mTOR signaling in vitro and in vivo. RB1CC1 acts tumor suppressive in inhibiting cell cycle progression and proliferation by RB1 induction, p53 stabilization, cyclin D1 destabilization, CP-358774 suppression of PyK2 and FAK, and STAT protein inhibition in vitro. Despite the frequent RB1CC1 deletion in primary human breast cancers, RB1CC1 conditional knockout in mamillary gland and skin failed to promote tumorigenesis.RB1CC1 plays complex roles in cellular pathways relevant to carcinogenesis. These reports indicate that the impact of RB1CC1 upon tumorigenesis differs depending upon context. The mRNA upregulation and relative rarity of RB1CC1 biallelic mutation observed in MSI-H colorectal tumors appears to support potential oncogenic roles of RB1CC1 in the colon. Consistent to this notion, the RB1CC1 locus is frequently amplified in CRCs. A putative RB1CC1-targeting micro-RNA,RAD001 miR-138, is a tumor-suppressor miR and downregulated in non-colonic malignancies. Taken together, it is speculated that RB1CC1 may act as an oncogene in large intestine, and that 39UTR MSI may serve as an upregulatory mechanism in place of genomic amplification in MSI-H cancers that typically lack chromosomal aberrations. In summary, we verified the strong dependency of MSI incidence upon microsatellite length in MSI-H colorectal tumors and, to a lesser degree, in MMR-proficient cells by conducting an extensive survey of well-characterized short 39UTR microsatel-lites. In contrast, relevance of a microsatellite to its corresponding gene functionality appeared to have little impact upon MSI incidence.