Colorectal cancer (CRC) remains a significant factor contributing to the morbidity and mortality rates linked with cancer throughout the world, especially in its stages of progression. Increasingly attractive therapeutic options include immune modulation combined with preoperative chemotherapy and radiation therapy (CRT). Recent studies have revealed that the protein serine peptidase inhibitor Kazal type 4 (SPINK4), which is abundantly expressed in gastrointestinal tract tissues, plays a role in immune evasion and treatment resistance in cancers. This meta-analysis aims to assess the relationship between SPINK4 expression levels and the therapeutic effectiveness of radiolabeled immune modulators in patients with advanced CRC who are undergoing preoperative chemotherapy and radiation treatment. The degree of SPINK4 expression and a lower objective response to radiolabeled immune modulators showed a statistically significant link. Conversely, patients with low SPINK4 expression have more favorable treatment responses and ongoing clinical improvement following CRT. High SpINK4 expression can act as a negative prognostic biomarker for radiolabeled immune control in advanced CRC.
LiY, LiY, LiW, et al.Genetic polymorphisms in serine protease inhibitor Kazal-type 5 and risk of atopic dermatitis: A meta-analysis. Medicine (Baltimore), 2020; 99(28):e21256; doi: 10.1097/MD.0000000000021256
2.
ZhangX, AiR, DingZ, et al.Identification and exploration of Serine Peptidase Inhibitor Kazal Type 1 (SPINK1) as a potential biomarker correlated with the progression of non-small cell lung cancer.
3.
LiD, ZhangX, DingZ, et al.Identification and exploration of serine peptidase inhibitor Kazal type I (SPINK1) as a potential biomarker correlated with the progression of non-small cell lung cancer. Cell Biochem Biophys, 2022; 80(4):807–818; doi: 10.1007/s12013-022-01098-w
4.
LvJL, LiQ, JiangJW, et al.The function of one type of Kazal-type serine protease inhibitor from Silkworms, Bombyx mori (Lepidoptera). J Asia Pac Entomol, 2025; 28(1):102386; doi: 10.1016/j.aspen.2025.102386
5.
WangS, SunY, ShaoD, et al.High expression of serine protease inhibitor Kazal type 1 predicts poor prognosis and promotes the progression and invasion of oral tongue squamous cell carcinoma. Arch Oral Biol, 2024; 164:106003; doi: 10.1016/j.archoralbio.2024.106003
6.
WangY, HanJ, YangG, et al.Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis. Nat Commun, 2024; 15(1):5874; doi: 10.1038/s41467-024-50048-y
7.
JiaJ, GaL, LiuY, et al.Serine protease inhibitor Kazal type 1, a potential biomarker for the early detection, targeting, and prediction of response to immune checkpoint blockade therapies in hepatocellular carcinoma. Front Immunol, 2022; 13:923031; doi: 10.3389/fimmu.2022.923031
8.
WangY, WangB, LiuM, et al.Characterization and function analysis of a Kazal-type serine proteinase inhibitor in the red claw crayfish Cherax quadricarinatus. Dev Comp Immunol, 2021; 114:103871; doi: 10.1016/j.dci.2020.103871
9.
ChangC, XieJ, YangQ, et al.Serine peptidase inhibitor Kazal type III (SPINK3) promotes BRL‐3A cell proliferation by targeting the PI3K–AKT signaling pathway. J Cell Physiol, 2020; 235(3):2209–2219; doi: 10.1002/jcp.29130
10.
MendesSR, Amo-MaestroLD, Marino-PuertasL, et al.Analysis of the inhibiting activity of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) on matrix metalloproteinases. Sci Rep, 2020; 10(1):6317; doi: 10.1038/s41598-020-63338-4
11.
LuF, OttC, BistaP, et al.Three-dimensional structure of novel liver cancer biomarker liver cancer-specific serine protease inhibitor Kazal (LC-SPIK) and its performance in clinical diagnosis of hepatocellular carcinoma (HCC). Diagnostics (Basel), 2024; 14(7):725.
12.
RojasL, Cabrera-MuñozA, PradasDG, et al.Arginine substitution by alanine at the P1 position increases the selectivity of CmPI-II, a non-classical Kazal inhibitor. Biochem Biophys Rep, 2021; 26:101008; doi: 10.1016/j.bbrep.2021.101008
SotoA, Perrone SibiliaM, SánchezVR, et al.Contribution of Kazal-like domains of the serine protease inhibitor-1 from toxoplasma gondii in asthma therapeutic vaccination effectiveness. Int Arch Allergy Immunol, 2022; 183(5):471–478.
15.
ChenYT, TsengTT, TsaiHP, et al.Serine protease inhibitor Kazal type 1 (SPINK1) promotes proliferation, migration, invasion and radiation resistance in rectal cancer patients receiving concurrent chemoradiotherapy: A potential target for precision medicine. Hum Cell, 2022; 35(6):1912–1927; doi: 10.1007/s13577-022-00776-4
16.
WuZ, TangM, ZhaoJ, et al.Genome-wide identification and immune response analysis of serine protease inhibitor genes in the blood clam Tegillarca granosa. Fish Shellfish Immunol, 2022; 131:1234–1244; doi: 10.1016/j.fsi.2022.11.036
17.
KulkeM, NagelF, SchuligL, et al.A hypothesized mechanism for chronic pancreatitis caused by the N34S mutation of serine protease inhibitor Kazal-type 1 based on conformational studies. J Inflamm Res, 2021; 14:2111–2119; doi: 10.2147/JIR.S304787
18.
BuchholzI, NagelF, KleinA, et al.The impact of physiological stress conditions on protein structure and trypsin inhibition of serine protease inhibitor Kazal type 1 (SPINK1) and its N34S variant. Biochim Biophys Acta Proteins Proteom, 2020; 1868(1):140281; doi: 10.1016/j.bbapap.2019.140281
19.
LuF, ShahPA, RaoA, et al.Liver cancer–specific serine protease inhibitor Kazal is a potentially novel biomarker for the early detection of hepatocellular carcinoma. Clin Transl Gastroenterol, 2020; 11(12):e00271; doi: 10.14309/ctg.0000000000000271
20.
LiuH, HuangQ, LvY, et al.CEBPB knockdown sensitizes nasopharyngeal carcinoma cells to cisplatin by promoting the expression of serine protease inhibitor Kazal-type 5. Anticancer Drugs, 2022; 33(1):e327–e335; doi: 10.1097/CAD.0000000000001208
21.
HuoX, GongX, MaL. Netherton syndrome caused by serine protease inhibitor of Kazal type 5 gene mutation: A case report and literature review. Chinese Journal of Perinatal Medicine, 2021:54–60.
22.
MaharjanA. Characterization and Gene Expression Analysis of Kazal-Type Serine Protease Inhibitors of Globisporangium ultimum (Master’s thesis, Bowling Green State University).
23.
SalvesenG, EnghildJJ. Proteinase inhibitors: an overview of their structure and possible function in the acute phase. Acute Phase Proteins Molecular Biology, Biochemistry, and Clinical Applications. 2020:117–47.
24.
ChenYR, YangHJ, LiZ, et al.Expression of Kazal-type serine protease inhibitor gene AgKaSPI in Aphis glycines (Hemiptera: Aphididae) in response to Akanthomyces lecanii infection. Acta Entomologica Sinica.
