The Function And Mechanism Research Of HPIP In Colorectal Carcinoma

Colorectal cancer (CRC) is one of the most common malignancies in the world and the third most frequent cause of cancer-related death in western societies, accounting for approximately 10% of all cancer incidence and mortality. Thus, elucidation of the molecular mechanisms underlying CRC tumorigenesis and progression is critical to individual treatment of CRC. Although it is widely accepted that CRC is a heterogeneous disease defined by different activating mutations in receptor tyrosine kinases (RTKs) or other mutations in downstream components of RTK-activated intracellular pathways, our understanding of the genetic alteration underlying the development of colorectal cancer remains limited.Human hematopoietic PBX-interacting protein (HPIP) was first identified by Abramovi-ch in fetal liver cDNA library using a yeast two hybridization strategy with pre-B-cell leu-kemia transription factor 1 (PBX1) as a bait in 2000. The full-length cDNA of HPIP encodes a 731-amino acid protein that has no significant homology to known proteins. It adjust the differentiation of hematopoietic stem cell and inhibit leukemia generation via inhibiting the transcription activation of E2A-PBX1, through binding PBX family and interacting with it.Our previous study found that breast cancer cells after translated into HPIP, its growth rate would be speeding up compared with the empty vector, at the same time, HPIP was detect widely expressed in cervical cancer, lung cancer, liver cancer cell line, suggested HPIP may participate in regulating cell positive growth proliferation, indicates that HPIP may be a cancer gene. However, the role of HPIP in colorectal cancer (CRC) is unknown。 It is not yet known whether inhibition of HPIP may be as a strategy for colorectal cancer treatment or not. As we know, at present, the cure rate of early colorectal cancer is as high as 90-100%, while the 5-year survival rate of the late CRC is only 10%. Early diagnose of CRC was based on the tumor makers such as carbohydrate antigen 199, carcinoma embr-yonic antigen, but these protein usually has a low sensitivity (probably 10-40%) and specificity. Thus, We decided to research the expression and mechanism of HPIP in colo-rectal carcinoma. Our present work suggests critical function and mechanism of HPIP in colorectal cancer for the first time First Using the imminghistochemical detcction HPIP is up-regulated in 64 colorectal cancer patients, in comparison to normal colorectal tissues, and predict the worse clinical outcome in CRC, the patients with high expression of HPIP had shorter disease-free survival (DFS) and overall survival (OS) than those with low expression of HPIP (DFS:p=0.011, OS:p=0.021). Second, HCT-116 cells transfected with FLAG-tagged HPIP grew much faster than those transfected with empty vector or parental HCT-116 cells. Similar results were obtained in SW480 cells infected with HPIP expressing lentivirus. HCT-8 and SW480 cells infected with HPIP shRNA grew more slowly than those infected with control shRNA or their parental cells, Then, HPIP promotes cell growth by inhibiting apoptosis and activation of cell cycle progression from Glto S phase and G2 to M phase, accompanied by changes in expression of apoptosis and cell cycle regulators. Morever, we find HPIP reducing sensitivity of CRC cells to Oxaplatin, a chemotherapy drug used for treatment of CRC. Finally, HPIP promotes cell migration and invasion with increased EMT, based on wound-healing and transwell invasion assays. Moreover, HPIP increases CRC cell proliferation and migration through activation of MAPK/ERK1/2 and AKT, for inhibition of ERK and AKT alleviated the ability of HPIP to regulate CRC cell proliferation and migration as well as the expression of the cell cycle regulators and the EMT markers. Finally, knockdown of HPIP can inhibit CRC cell growth in nude mice. These findings indicate that HPIP may play an important role in the development and progression of colorectal cancer.