The Role of Inter-Alpha-Trypsin-Inhibitor-Heavy-Chain-5 (ITIH5) in Suppressing Pancreatic Cancer Metastasis

Abstract

Metastasis is the spread of cancer from the site of origin to a distant site, where the colony of malignant cells grows. Growth of malignant cells in secondary sites disrupts organ function and increases the tumor burden on the host. Thus, there is a critical need to understand the factors regulating the spread of cancer cells to distant sites and their growth therein. Over half of all patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) present with liver metastasis, and five-year survival for these patients is currently three percent. We performed an in vivo screen for PDAC metastasis suppressors using a human whole-genome shRNA library in order to understand factors regulating PDAC metastasis and identified Inter-α-Trypsin Inhibitor Heavy Chain 5 (ITIH5) as a suppressor of PDAC metastasis. Knockdown of ITIH5 significantly increased liver metastasis while high ITIH5 expression was correlated with rounded cell morphology and decreased cell motility and metastasis. ITIH5 is a secreted protein related to plasma protease inhibitors. To test the hypothesis that secretion of ITIH5 is required to suppress metastasis, we deleted the secretion signal sequence of ITIH5 (ITIH5Δs) and compared development of liver metastasis in highly metastatic PDAC cells expressing either control vector, secreted ITIH5, or secretion-deficient ITIH5Δs. Intriguingly, ITIH5Δs was sufficient to recapitulate the effects of secreted ITIH5 on cell morphology, motility and metastasis. These data suggest that ITIH5 may suppress metastasis by an intracellular mechanism not predicted by previously published reports. Understanding how intracellular ITIH5 attenuates PDAC metastasis could reveal new elements of PDAC biology that could become future therapeutic targets for patients affected by this aggressive cancer.