Cooperation of SRPK2, Numb and p53 in the malignant biology and chemosensitivity of colorectal cancer

Abstract

Serine-arginine protein kinase 2 (SRPK2) is aberrantly expressed in human malignancies including colorectal cancer (CRC). However, little is known about the molecular mechanisms, and the role of SRPK2 in chemosensitivity remains unexplored in CRC. We recently showed that SRPK2 promotes pancreatic cancer progression by down-regulating Numb and p53. Therefore, we investigated the cooperation between SRPK2, Numb and p53 in the cell migration, invasion and chemosensitivity of CRC in vitro. Here, we showed that SRPK2 expression was higher in CRC tumors than in nontumor tissues. SRPK2 expression was positively associated with clinicopathological characteristics of CRC patients, including tumor differentiation, T stage, N stage and UICC stage. Additionally, SRPK2 had no association with mutant p53 (mtp53) in SW480 and SW620 cells, but negatively regulated Numb and wild-type p53 (wtp53) in response to 5-fluorouracil or cisplatin treatment in HCT116 cells. Moreover, SRPK2, Numb and p53 coimmunoprecipitated into a triple complex with or without the treatment of 5-fluorouracil in HCT116 cells, and p53 knockdown reversed the up-regulation of wtp53 induced by SRPK2 silencing with chemical agent treatment. Furthermore, overexpression of SRPK2 increased cell migration and invasion and decreased chemosensitivity to 5-fluorouracil or cisplatin in HCT116 cells. Conversely, SRPK2 silencing decreased cell migration and invasion and increased chemosensitivity to 5-fluorouracil or cisplatin, yet these effects could be reversed by p53 knockdown under chemical agent treatment. These results thus reveal a novel role of SRPK2-Numb-p53 signaling in the progression of CRC and demonstrate that SRPK2 is a potential therapeutic target for CRC clinical therapy.

Numb-PRRL promotes TGF-β1- and EGF-induced epithelial-to-mesenchymal transition in pancreatic cancer

“…Meanwhile, Numb-PRRS overexpression was associated with tumor high differentiation, indicating its pro-differentiation and tumor-suppressive role in the progression of PC based on our current and previous studies [ 19 , 20 , 25 ]. Interestingly, Numb-PRRL was overexpressed in hepatocellular carcinoma [ 14 ], medulloblastoma [ 10 , 26 ] and invasive urothelial carcinoma of the bladder [ 27 ], but exhibited low expression in breast [ 11 ] and lung cancers [ 12 ]. Therefore, the unbalanced distribution of Numb isoforms contributes to the distinguished role of total Numb protein in cancers.…”

“…It displayed complex and multiple functions including the control of asymmetric cell division and cell fate choice, endocytosis, cell adhesion and migration, ubiquitination of specific substrates, and a variety of signaling pathways (Notch, Hedgehog, MDM2-p53, and WNT signaling) [ 8 – 10 ]. Accumulated evidence showed that Numb acts as a tumor-suppressive role in medulloblastoma [ 10 ], breast cancer [ 11 ], non-small cell lung cancer (NSCLC) [ 12 ], ovarian cancer [ 13 ], and colorectal cancer [ 14 ]. On the other hand, overexpression of Numb was found in hepatocellular carcinoma [ 15 ], astrocytomas [ 16 ], and cervical squamous carcinoma cells [ 17 ].…”

Therapeutic Targeting of Alternative Splicing: A New Frontier in Cancer Treatment

“…Evidence seems to suggest that SRPK2 plays a similar oncogenic role, albeit not much is known about SRSF2 compared to SRSF1. Most recently, SRPK2 expression was shown to be higher in colorectal cancer tumors compared to nontumor tissues, and was positively associated with tumor differentiation, primary tumor (T) stage, regional lymph nodes (N) stage, and UICC stage (59). The same authors showed that SRPK2 promotes pancreatic cancer progression by downregulating Numb and p53, and this negative regulation also occurred following 5-fluorouracil or cisplatin treatment in colorectal cancer cells [ (37,59).…”

“…Most recently, SRPK2 expression was shown to be higher in colorectal cancer tumors compared to nontumor tissues, and was positively associated with tumor differentiation, primary tumor (T) stage, regional lymph nodes (N) stage, and UICC stage (59). The same authors showed that SRPK2 promotes pancreatic cancer progression by downregulating Numb and p53, and this negative regulation also occurred following 5-fluorouracil or cisplatin treatment in colorectal cancer cells [ (37,59). Overexpression also increased cell migration and invasion, and decreased chemosensitivity to 5fluorouracil or cisplatin (59).…”

“…The same authors showed that SRPK2 promotes pancreatic cancer progression by downregulating Numb and p53, and this negative regulation also occurred following 5-fluorouracil or cisplatin treatment in colorectal cancer cells [ (37,59). Overexpression also increased cell migration and invasion, and decreased chemosensitivity to 5fluorouracil or cisplatin (59). The functions of SRPK1-2 in cancer are understood to a much greater extent than SPRK3.…”