HIPK2 inhibits cell metastasis and improves chemosensitivity in esophageal squamous cell carcinoma

Abstract

Abstract. Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive and lethal malignancies worldwide. At present, the underlying mechanisms of ESCC development and progression are poorly understood. Previous studies have demonstrated that homeodomain-interacting protein kinase-2 (HIPK2) serves an important role in cancer biology, particularly in proliferation and metastasis. However, the role of HIPK2 in ESCC cells remains unclear. In the current study, the expression of HIPK2 in ESCC specimens, adjacent non-cancerous tissues and cell lines was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The effects of HIPK2 on cell metastasis, epithelial-mesenchymal transition (EMT) and proliferation were studied using a Transwell assay, RT-qPCR and a Cell Counting Kit-8 assay, respectively. The results indicated that HIPK2 expression was downregulated in ESCC specimens and cell lines, and HIPK2 expression was associated with tumor invasion and lymph node metastasis. Functional studies demonstrated that HIPK2 overexpression inhibited cell metastasis and EMT. Furthermore, HIPK2 overexpression suppressed cell viability during cisplatin treatment. These results suggest that HIPK2 serves an important role in regulating metastasis and the chemosensitivity of ESCC cells, implicating the potential application of HIPK2 in ESCC therapy. IntroductionEsophageal squamous cell carcinoma (ESCC) is one of the most aggressive and lethal malignancies worldwide (1). Nutritional deficiencies, nitrosamine-rich or mycotoxin-contaminated foods and low socioeconomic status are likely to contribute to ESCC (1,2). It has been reported that heavy smoking and alcohol consumption are key environmental risk factors for ESCC (3,4). Dysphagia is the most common symptom of ESCC. Although surgery is considered to be the most effective treatment for ESCC in terms of locoregional control and long-term survival, recurrence and metastases to the liver occur in the majority of cases following complete resection, resulting in a 15-25% five-year survival rate in patients with ESCC (5). Therefore, the identification of molecular mechanisms that pinpoint biologically aggressive tumors is critical for the effective management of ESCC.Homeodomain-interacting protein kinase-2 (HIPK2) is a member of an evolutionary conserved family of serine/threonine kinases and is considered to be a tumor suppressor that modulates a number of basic cellular processes, including apoptosis, proliferation, differentiation and metastasis (6-9). It has previously been demonstrated that HIPK2 mediates apoptosis and epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells contributing to fibrosis, implying that it may be a potential target for anti-fibrosis therapy (10). HIPK2 has also been demonstrated to activate the p53 protein via direct binding and phosphorylation at serine 46 following severe DNA damage (11). Puca et al (12) demonstrated that HIPK2 is an important regulator of p53 activity in response to chemothera...

Homeodomain‐interacting protein kinase 2 suppresses proliferation and aerobic glycolysis via ERK/cMyc axis in pancreatic cancer

“…HIPK2 can be activated by several forms of genotoxic damage, such as UV radiation, ionizing radiation or antitumour drugs like cisplatin, leading to expression of proapoptotic genes. [29][30][31] Therefore, decreased HIPK2 expression in cancer might play certain roles in resistance to chemotherapy and radiotherapy. Further investigations to demonstrate the role of decreased HIPK2 in pancreatic cancer chemotherapy and radiotherapy resistance are needed.…”

Cell Fate Regulation upon DNA Damage: p53 Serine 46 Kinases Pave the Cell Death Road

“…AMPK shows an overall mutation rate of 2.1–3% (for the two isoforms of the catalytic subunit, respectively), ATM of 6%, DYRK2 of 2.7%, HIPK2 of 2.9%, p38α of 1.4%, and PKCδ of 1.7% (assessed via http://cbioportal.org). Reduced expression of the p53 Ser46 kinases in human tumors has been reported for four of the kinases: ATM in hormone‐negative breast cancer and non‐ small cell lung cancer; DYRK2 in colorectal cancer, hepatocellular carcinoma, and breast cancer; HIPK2 in oesophageal squamous cell carcinoma; and PKCδ in colon cancer . However, since the function of kinases depends on their specific activity and a number of Ser46 kinases, including DYRK2, HIPK2, PKCδ, and p38α, are regulated by their subcellular localization, it will be a complex task to determine their potential deregulation in cancer.…”

Inactivation of homeodomain‐interacting protein kinase 2 promotes oral squamous cell carcinoma metastasis through inhibition of P53‐dependent E‐cadherin expression

“…These results suggested an effective function of HIPK2 deficiency in promoting tumor metastasis. Although previous studies have confirmed that suppressing HIPK2 mediates tumor invasion and metastasis in several malignancies, 15,31‐33 the mechanisms are not well defined. To our knowledge, only two signaling pathways involved in HIPK2 that oppose tumor invasion have been reported, including suppressing β4 integrin transcription 43 and promoting β‐catenin nuclear localization 15 .…”

“…29,30 Recently, emerging lines of evidence has suggested that HIPK2 might have other functions that oppose the epithelial-mesenchymal transition (EMT) process, and thus HIPK2 might inhibit tumor invasion and metastasis. 15,17,[31][32][33] However, the mechanisms involved in HIPK2-mediated tumor invasion and metastasis have not been fully elucidated, and the signaling pathways vary in different cancer types. For example, HIPK2 knockdown could induce Wnt signaling activation and β-catenin nuclear localization, and thus promote EMT and subsequent cell invasion in bladder cancer.…”

“…As an effective activator of P53, the classical role of HIPK2 is to respond to various stress signals, thus inducing cell cycle arrest and apoptosis 29,30 . Recently, emerging lines of evidence has suggested that HIPK2 might have other functions that oppose the epithelial‐mesenchymal transition (EMT) process, and thus HIPK2 might inhibit tumor invasion and metastasis 15,17,31‐33 . However, the mechanisms involved in HIPK2‐mediated tumor invasion and metastasis have not been fully elucidated, and the signaling pathways vary in different cancer types.…”