Protein Cell: Jiang Hai/Zhang Lei team-finding new primary cancer gene and hippo pathway new regulatory factor SHANK2.

An important way to activate the gene of the central cancer of cancer cells is to obtain an increase in the number of copies of the gene by the regional amplification of the chromosome segment in which it is located.
classic primary cancer genes such as c-Myc, HER2, SKP2, etc. are mainly activated in this way.
, however, the region amplification of chromosomes is not an accurate process, and in the vast majority of tumors there are several or even hundreds of genes near the original cancer gene that are incidental amplification (co-a-enhanced).
therefore, the conclusions are still unclear as to which of some chromosomal amplification segments of the tumor, which are the primary cancer genes that drive the tumor, and which are the genes that are incidentally amplified.
in response to this problem, a more intuitive inference is that since the primary cancer gene amplification is an intrinsic progenitor to the tumor, its amplification should appear in all tumor samples with the amplified segment of the chromosome.
therefore, the systematic analysis of the frequency of the amplification of various genes in a cancer-promoting chromosome region of the tumor, of which the most frequently amplified genes may be the primary cancer gene that promotes the tumor.
however, previous lysate data from cancer gene amplification was small and dispersed, making it difficult to provide enough sample sizes to ensure the resolution of the above analysis.
the recent accumulation of tumor genome data provides a new opportunity to solve this problem.
July 13, 2020, jiang Hai's research group at the Center for Excellence in Molecular Cell Science (CSO) of the Chinese Academy of Sciences, in collaboration with Zhang Lei of the Center for Excellence in Molecular Science, in collaboration with Zhang Lei's research group in the journal Protein and Cell, published an article "SHANK2 is a frequently a bedly amplified oncocoe with evolutionarily conserved conves in s.
Jiang Hai's team summarized the amplification of all protein-coding genes in more than 14,000 tumor genomes from the COSMIC Tumor Genome Database, and compared them with the chromosome segments in which each gene is located, resulting in a high-resolution control data set of tumor gene amplification - chromosomal coding locations. On this basis, the primary cancer gene in each chromosome amplification region is predicted
.
these analyses, 11q13 is the second most frequently amplified chromosomal segment in human tumors, but the highest amplification frequency is not the traditionally thought cell cycle regulatory factor Cyclin D1 (CCND1), but the previously undiscovered cancer-promoting SHANK2 gene, the number of tumor samples amplification of the latter is nearly twice the former.
this suggests that SHANK2 may be a new potential primary cancer gene.
coincidence, when Zhang Lei's team screened the new regulatory factors of HIPPO signaling pathways in fruit flies, it was found that sHANK2's homologous gene had been expressed in fruit flies, triggering a very significant epicurrentalation of HIPPO pathway inactivation and cell overproliferation.
this suggests that SHANK2 may interfere with the HIPPO pathway, thereby promoting cell proliferation and cancer.
combined with this discovery, Jiang Hai's team analyzed the pro-cell proliferation effect of SHANK2 in mammalian cells, used several mouse tumor models to confirm the tumor-promoting effect of SHANK2, verified the ability of SHANK2 to regulate THE pathway, and expounded its molecular mechanism.
studies show that SHANK2, through its PDZ domain, competes competitively with ARHGEF7, preventing it from binding to LATS1, resulting in a decrease in the degree of phosphorylation of YAP.
removed the PDZ domain, SHANK2 was no longer able to inhibit HIPPO pathway activity and lost its ability to promote tumors.
in addition, in SHANK2 over-expression of tumor cell lines, the reduction of SHANK2 can restore hippo pathway activity and completely inhibit cell proliferation and tumor-forming capacity in naked mice.
this suggests that SHANK2 may be a new potential therapeutic target.
because SHANK2 is expressed only in the nervous system in adults and is not involved in the proliferation of normal cells of peripheral tissues, as a potential therapeutic target, the blood-brain barrier may be used to achieve low-toxic cancer treatment.
SHANK2 as an autism-related gene, and previous studies have focused on its role in the nervous system.
the study for the first time, sHANK2 is an unknown primary cancer gene.
the study also showed that SHANK2 is an evolutionaryly conservative HIPPO pathway regulator and points to new ways for tumor cells to escape HIPPO to suppress cancer effects.
it is understood that Xu Liang, a doctoral student in Jianghai's research group, is the first author, And Li Peixuan, Feng Xue and Lu Yi of Zhang Lei's team completed the research work in fruit flies, and Jiang Hai and Zhang Lei are co-authors of the study.
noteworthy, although CyclinD1 has long been considered the main driver on 11q13, 11q13 amplification of tumors is clinically insensitive to CyclinD-CDK4/6 inhibitors.
a recently published protein staining study of tumor samples also found that SHANK2 was expressed in nearly 80 percent of esophageal cancer samples with amplification of 11q13, while only 25 percent of the same 11q13 amplification samples had expressed Cyclin D1, suggesting that additional, independent cyclinD1 drivers may be present in the 11q13 segment.
the study found that SHANK2 could fill this possibility by systematically analyzing gene amplification in tens of thousands of tumor samples and combining it with gene chromosomal localization.
In addition to SHANK2, there are some potential new primary cancer genes in the remaining chromosome amplification segments of the tumor. similar methods
can also be used in the study of cancer-suppressing genes in tumor chromosome deletion regions.
.