The heterogeneous nuclear ribonucleoprotein (hnRNP) K is an essential RNA and DNA binding protein involved in gene expression and signal transduction including DNA transcription, RNA splicing, RNA stability and translation. The role of hnRNP K in cancer is relatively understudied. However, several cellular functions strongly indicate that hnRNP K is involved in tumorigenesis. In this study, we investigated the altered protein expression and the subcellular distribution of the hnRNP K protein using tissue microarrays in pancreatic cancer. We showed an increased cytoplasmic hnRNP K in pancreatic cancer. This increase in hnRNP K protein occurs at the posttranscriptional level. We postulate that the cytoplasmic accumulation of hnRNP K will lead to silenced mRNA translation of tumor suppressor genes and thus contributes to pancreatic cancer development. We also demonstrated that knocking down of hnRNP K expression by siRNA inhibited pancreatic cancer cell growth and colony formation. hnRNP K was identified as a member of the p53/HDM2 pathway. Whether hnRNP K interacts with the mutant p53 is not known. Using two different pancreatic cancer cell lines, we can demonstrate that hnRNP K interacts with the mutant p53. The subcellular distribution and function of the mutant p53 and the interaction of hnRNP K/mutant p53 were affected by the Ras/MEK/ERK pathway, growth factors and the specific p53 mutations in pancreatic cancer cells. Since Kras is activated and p53 is mutated in most pancreatic cancers, these data unveiled an important new signaling pathway that linked by hnRNP K and mutant p53 in pancreatic cancer tumorigenesis.