SPOCK1 is up-regulated and promotes tumor growth via the PI3K/AKT signaling pathway in colorectal cancer

Highlights

• SPOCK1 expression is significantly up-regulated in CRC tissues and associated with tumor size and TMN stage.

• Down-regulation of SPOCK1 suppresses CRC cell proliferation both in vitro and in vivo.

• SPOCK1 stimulates the PI3K/AKT signaling pathway to inhibit cell apoptosis and promote tumor growth.

Abstract

SPOCK1 encodes a Ca²⁺-binding matricellular glycoprotein which plays an oncogenic role in cancer cells. However, the role of SPOCK1 in the pathogenesis of colorectal cancer (CRC) has not been determined. Here, SPOCK1 was found higher expressed in CRC tissues than that of adjacent normal tissues. Furthermore, up-regulated expression of SPOCK1 in CRC patients was associated with tumor size and TNM stage. In addition, we observed that the depletion of SPOCK1 inhibited proliferation in vitro and tumorigenicity in vivo and promoted apoptosis in cell culture. Our data suggest that inactivation of PI3K/Akt signaling pathway was involved in down-regulation of SPOCK1-mediated suppression of tumor cell proliferation. These results suggest that SPOCK1 expression is correlated with malignant features of CRC and may serve as potential therapeutic and preventive strategies for CRC.

Introduction

Colorectal cancer(CRC) is one of the most common malignant cancers, the third leading cause of cancer-related death in men(746,000 cases, 10% of all cancers), the second leading cause of cancer-related death in women (614,000 cases, 9.2% of all cancers), and approximately 600,000 people died of CRC annually worldwide [1]. The increasing prevalence of virulence factors for CRC such as dietary factors, obesity, environmental exposures, genetic susceptibility and smoking are gradually being determined [2], [3]. Despite advances in early detection, surgical techniques, chemotherapy, radiotherapy, molecular targeted therapy have increased the prognosis of CRC patient, the 5-year survival rate is less than 40% in less developed countries, including China [4]. Molecular signaling and proliferation of tumors have also been shown to be closely associated with CRC, but the molecular mechanisms underlying CRC carcinogenesis are still under investigation. Thus, novel molecular biomarkers to better understand CRC proliferation as well as cancer therapeutic targets should be explored.

The SPARC/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) was first identified in human testicular seminal plasma, which encodes a Ca²⁺-binding matricellular glycoprotein that belongs to the SPARC family [5], [6]. SPOCK1, as well as other members of this family, which shares a similar structure that consists of N-terminus, follistatin-like domain, and C-terminus, and plays crucial roles in cell proliferation, cell–cell adhesion and migration [7]. Accumulating evidence has confirmed that amplification of SPOCK1, as well as mRNA and protein overexpression, involves in the regulation of cell cycle control, apoptosis, and metastasis, which has been frequently shown in various human malignancies, such as prostate, gallbladder, lung carcinomas [8], [9], [10]. However, to the best of our knowledge, information on the relationship between SPOCK1 and CRC, including the molecular mechanisms and clinical potentials underlying the participation of SPOCK1 in these malignant features, are limited.

In the current work, we first revealed that expression of SPOCK1 was up-regulated in CRC patients. Second, we show that SPOCK1 depletion effectively inhibits cell proliferation in vitro and significantly suppresses tumor growth in vivo. In addition, cell proliferation was suppressed by inducing cell cycle arrest at the G0/G1 phase in SPOCK1-knockdown cells. Last, we demonstrate that the PI3K/AKT pathway is involved in the oncogenic function of SPOCK1-mediated cell survival. This research provided new understanding into the pathogenesis of CRC which will constitute a potential biomarkers and aid novel therapeutic strategies.