Suppression of pancreatic cancer growth and metastasis by HMP19 identified through genome‐wide shRNA screen

Abstract

Therapeutic effectiveness against metastatic or even locally advanced pancreatic ductal adenocarcinoma (PDAC) is dismal, with 5-year survival less than 5%. Even in patients who undergo potentially curative resection, most patients’ tumors recur in the liver. Improving therapies targeting or preventing liver metastases is crucial for improving prognosis. To identify genes suppressing metastasis, a genome-wide shRNA screen was done using the human non-metastatic PDAC cell line, S2-028. After identification of candidates, functional validation was done using intrasplenic and orthotopic injections in athymic mice. HMP19 strongly inhibited metastasis but also partially attenuated tumor growth in the pancreas. Knockdown of HMP19 increased localization of activated ERK1/2 in the nucleus, corresponding to facilitated cell proliferation, decreased p27Kip1 and increased cyclin E1. Over-expression of HMP19 exerted the opposite effects. Using a tissue microarray of 84 human PDAC, patients with low expression of HMP19 showed significantly higher incidence of liver metastasis (P = 0.0175) and worse prognosis (P = 0.018) after surgery. HMP19, a new metastasis/tumor suppressor in PDAC, appears to alter signaling that leads to cell proliferation and appears to offer prognostic value in human PDAC.

Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer

“…1B and 3A). We recently reported functionality and preliminary mechanistic characterization of HMP19 [19]. In this study, we focused on ITIH5.…”

“…Using a forward genetic screen using a genome-wide RNAi library and a non-metastatic S2-028 PDAC cell line, we identified two novel metastasis suppressor candidates, ITIH5 and HMP19. The latter was recently validated as a metastasis suppressor [19] and ITIH5 was functionally characterized in this study.…”

ITIH5 induces a shift in TGF‐β superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death

“…Recently, the working group of Danny R. Welch who had characterized the metastasis suppressor gene KISS1 in breast cancer, proposed ITIH5 as novel metastasis suppressor in pancreatic ductal carcinoma. By performing a genome‐wide shRNA library screen consisting of 74 468 shRNA directed against 21 416 human genes, ITIH5 was identified as one of two genes whose knockdown enabled the non‐metastatic PDAC cell line S2‐028 to metastasize to the liver using an intrasplenic injection mouse model …”

“…By performing a genome-wide shRNA library screen consisting of 74 468 shRNA directed against 21 416 human genes, ITIH5 was identified as one of two genes whose knockdown enabled the nonmetastatic PDAC cell line S2-028 to metastasize to the liver using an intrasplenic injection mouse model. 21,56 In the current study we aimed at specifying the role of ITIH5 in 33 in vitro. In addition, genes known to promote metastasis like S100A4 48 were inversely regulated with ITIH5.…”

Microarray Analysis of the Expression Profile of Long Non-Coding RNAs Indicates lncRNA RP11-263F15.1 as a Biomarker for Diagnosis and Prognostic Prediction of Pancreatic Ductal Adenocarcinoma

“…Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating malignancies with a 5-year survival rate less than 5% 1 . Early diagnosis in combination with comprehensive therapies including surgical resection, adjuvant chemotherapy and radiotherapy can increase the 5-year survival rate significantly 2 .…”