The paper “High SPINK1 expression predicts poor prognosis and promotes cell proliferation and metastasis of hepatocellular carcinoma” evaluates the prognostic value and role of serine protease inhibitor Kazal type I (SPINK1) in the proliferation and metastatic potential of hepatocellular carcinoma (HCC) [Citation1]. The identity of SPINK1 is that of a small secreted protein, which, however, could be characterized by many in the scientific world as “double-faced”, since in different environments and situations it can have very different, if not opposing, roles. Specifically, on one hand in its role as a pancreatic secretory trypsin inhibitor that is produced by pancreatic acinar cells, it can prevent organ damage in pancreatitis by inhibiting early activation of trypsinogen to trypsin [Citation2]. As a result, mutations of SPINK1 lead to episodes of chronic pancreatitis and/or pancreatic insufficiency [Citation3]. On the other hand, when SPINK1 is found outside the normal pancreas, and especially in a tumor microenvironment, it has been shown to be over expressed by a significant number of different tumor cells, including prostate, breast, pancreas and colon, while at the same time it has been intimately associated with chemoresistance and increased risk of tumor recurrence [Citation4, Citation5]. The dual roles of SPINK1 make it an ideal target for therapeutic interventions; however, before that happens, it is essential to understand its identity and function better. Specifically, it would be useful to elucidate the mechanisms involved in its versatile function.
Huang et al. [Citation1] in this paper show us that high SPINK1 expression predicts poor prognosis and is possibly involved in metastasis in hepatocellular carcinoma. What is more important is the fact that they investigate and present possible mechanisms involved, including HCC cell proliferation, migration and invasion, as well as involvement of glycine, serine, threonine and bile acid metabolism. This will be critical in the effort to identify targets for a more precise approach against HCC. In addition, the authors are able to achieve their goals using an elegant experimental plan with the combination of tissue micro-arrays to identify the differential expression between HCC and normal tissue, as well as by using the Cancer Genome Atlas (TCGA) database and Gene set enrichment analysis (GSEA) to verify the prognostic value of SPINK1 in HCC. The importance of this lies in the fact that it showcases how molecular analysis and targeting can lead to a more patient-targeted, personalized approach, which is the essential goal of precision medicine.
Get personal!
Hepatocellular carcinoma represents the most frequent primary liver cancer, and in the global stage is the fourth most common cancer-related cause of death, something which will increase according to the World Health Organization to 1 million patients dying from HCC in 2030 [Citation6]. All of this makes HCC a serious global threat with increasing incidence, despite our improved understanding of the disease, as one of the things that is increasingly becoming clear with HCC is that it is an aggressive malignancy with significant heterogeneity. Essentially, any successful current and future attempts to treat HCC will have more to do with identifying molecular targets at different stages of the development and progression of the disease, rather than with a surgical approach.
Part of the problem, and at the same time part of the solution, is the fact that the interaction of precision oncology and molecular classification occurs at several levels in the case of HCC. Specifically, starting with genetic predisposition and the role of single nucleotide polymorphisms (SNPs), followed by endogenous and exogenous mutational processes and the accumulation of genetic and epigenetic alterations, are all important steps in the pathogenesis and development of HCC [Citation7]. Adding to this, there is the need to integrate and correlate all this data together with the clinical and pathological elements, in a clinically meaningful manner.
This last point highlights some of the existing obstacles in the pursuit of personalized medicine. Specifically, there is the need to be able to accumulate and evaluate significant amounts of data with the use of genetic databases, such as the Cancer Genome Atlas in this paper. The use and analysis of “Big Data” necessitates the integration of machine learning and artificial intelligence as an essential tool in the fight against cancer. Additionally, obtaining these huge amounts of data is not always easy given the scarcity of tissue, especially for advanced disease. The use of liquid biopsies could potentially improve the accumulation of circulating biomarkers, although what is really needed are better preclinical models, which will involve cell cultures that would take into consideration the tumor microenvironment.
Overall, this paper serves as an example of the importance of using biomarkers and molecular techniques to clarify the development and progression of a cancer, with an eye to identifying potential therapeutic targets. Moreover, it really shows us future avenues of how meaningful research efforts will evolve and the need for integrated care.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
- Huang K, Xie W, Wang S, et al. High SPINK1 expression predicts poor prognosis and promotes cell proliferation and metastasis of hepatocellular carcinoma. J Invest Surg. 2021;34(9):1011–1020. doi: 10.1080/08941939.2020.1728443
- Raphael KL, Willingham FF. Hereditary pancreatitis: current perspectives. Clin Exp Gastroenterol. 2016;9:197–207. doi:10.2147/CEG.S84358.
- Rasanen K, Itkonen O, Koistinen H, Stenman UH. Emerging roles of SPINK1 in cancer. Clin. Chem. 2016; 62 (3):449–457.
- Venet T, Masson E, Talbotec C, et al. Severe infantile isolated exocrine pancreatic insufficiency caused by the complete functional loss of the SPINK1 gene. Hum. Mutat. 2017; 38 (12):1660–1665. doi:10.1002/humu.23343.
- Chen F, Long Q, Fu D, et al. Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance. Nat. Commun. 2018; 9 (1):4315.
- Villanueva A. Hepatocellular Carcinoma. Review Article. N Engl J Med. 2019; 380(15):1450–1462. doi:10.1056/NEJMra1713263.
- Rebouissou S, Nault JC. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol. 2020; 72(2):215–229. doi:10.1016/j.jhep.2019.08.017.