21q22.3

CPI-B,CST6,EPM1,EPM1A,PME,STFB,ULD

Invasive cancers

Higher levels of stefin B in tumours have been determined in lung, breast, head and neck and prostate cancer as well as in murine lymphosarcomas, hepatomas and Lewis lung carcinomas. These higher levels, up to a certain level, may counter-balance the excessive activity of cysteine cathepsins, associated with matrix remodelling resulting in the progression of the disease. On the other hand, high cytosolic levels of stefins may be relevant for regulation of apoptosis, when initiated via lysosomal cell death pathway inhibiting cathepsin B, which was proposed as a dominant execution protease in the lysosomal apoptotic pathways, induced in a variety of tumour cells by tumour necrosis factor alpha ( TNF-alpha ). In some studies lower levels of stefins in tumours have been reported. Lower mRNA levels of stefin B have been reported in breast and esophagus tumours as compared to adjacent control tissues.
Although stefins are cytosolic proteins, they have also been detected in body fluids of cancer patients. Stefin B has been detected in ascitic fluid from patients with ovarian carcinoma and in bronhoalveolar fluid of lung cancer patients.
Diagnosis: The poor survival rate of hepatocellular carcinoma is in part due to the inability to diagnose patients at an early stage. Stefin B is specifically overexpressed in most hepatocellular carcinoma and is also elevated in the serum of a large proportion of hepatocellular carcinoma patients. Stefin B may be a useful marker for diagnosing patients with hepatocellular carcinoma with a high sensitivity.

Higher levels of stefin B in tumour tissues have been shown to correlate with a favourable prognosis of cancer patients. A significant prognostic value of stefin B was determined in patients with lung and head and neck cancer. On the other hand, animal model with excluded expression of stefin B did not support its suppressive function in cancer. A significantly lower metastatic spread was detected in stefin B knock-out mice than in wild-type animals. Similarly, higher levels of stefin B in body fluids have been associated with a poor prognosis of cancer patients. Alterations in secretion may result in higher extracellular and lower intracellular levels of stefins and, therefore, a reverse correlation with patient survival is to be expected.

Increased levels of cysteine protease activity, not being balanced by a corresponding increase of cysteine protease inhibitors are associated with progression of malignant disease and poor patients prognosis. Enhanced expression of stefin B would be expected to diminish the tumour-associated proteolytic activity and indeed, there is evidence of a suppressive role of stefin B in various cancer types.

Progressive myoclonus epilepsy

The progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is an autosomal recessive disease characterized by progressive myoclonic jerks and decline in cognition. Genetic linkage studies, suggest the involvement of the stefin B gene. A decreased amount of stefin B mRNA is a common finding in EPM1 patients and it may be due to: 1) a mutation in the promoter region causing a decrease in the rate of transcription of the gene or 2) mutations of the coding region/splice sites that may inhibit translation or diminish the half-life of the transcript and/or of the protein. The availability of a stefin B knock-out mouse as a model for the disease has allowed identification of the presence of severe apoptotic damage to the cerebellar granule cells. This observation combined with the anti-protease function of stefin B protein has suggested that it may have an anti-apoptotic function in the cerebellum. It was shown that a number of proteins (manly proteins that are involved in the regulation of cytoskeletal functions) that are not proteases can interact specifically with stefin B, forming a multiprotein complex. The first hypothesis is that stefin B may be active as antiprotease, protecting the complex against the attack of proteases. An alternative hypothesis is that stefin B may bind to the interacting proteins modifying the structure, thus allowing the correct formation of the complex. A further hypothesis is the sequestration of stefin B by the multiprotein complex, thus impeding its interaction with cathepsins.